Strengthening the EU Health Technology Assessment Regulation: Integrating National Immunization Technical Advisory Groups for Comprehensive Vaccine Assessments

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This paper's aim is to explore gaps from not involving National Immunization Technical Advisory (NITAG) Groups of European Member States into the recently adopted Health Technology Assessment regulation of the EU (EU HTAR), and propose strategies to involving them. 

Two methods are deployed to answer the research question: a literature review and guideline analysis, and a case study of three studies that have distinct approaches in how they involve NITAGs in national HTA processes. 

NITAGs are proposed to be included in EU HTAR only by 2030. Why? Can the authors summarize the possible reasons behind that decision?

Little detail is provided on the methodology of the literature review, for example, the search string is not presented, and neither are inclusion and exclusion criteria for the review. In the results, no information on number and types of reviewed studies is provided, and there is no systematic data extraction. The methodology of the case studies is similarly unclear. This puts to question the reproducibility of the study. 

In my assessment the paper is an editorial or opinion piece, rather than a research paper. I would suggest the authors add more detail on their research methods, and their findings, in a systematic way. Otherwise, they may want to consider rewriting it more squarely as an opinion piece. 

Author Response

Response to Reviewers

Manuscript title: Strengthening the EU HTA Regulation: Integrating NITAGs for Comprehensive Vaccine Assessments

Reviewer 1

This paper's aim is to explore gaps from not involving National Immunization Technical Advisory (NITAG) Groups of European Member States into the recently adopted Health Technology Assessment regulation of the EU (EU HTAR), and propose strategies to involving them.  

Two methods are deployed to answer the research question: a literature review and guideline analysis, and a case study of three studies that have distinct approaches in how they involve NITAGs in national HTA processes.  

NITAGs are proposed to be included in EU HTAR only by 2030. Why? Can the authors summarize the possible reasons behind that decision? 

The EU HTAR will become applicable to different medicinal products in phases. The Regulation became first applicable for oncology products and advanced therapy medicinal products in January 2025, and vaccines will be introduced last, in 2030. So far, vaccine specifics are not yet included in the EU HTAR, and also NITAGs, as specialized vaccine-bodies providing evidence-based vaccine recommendations, are not yet involved. The European Commission has not provided a specific explanation for this decision. However, possible reasons could include the need for additional time to coordinate and integrate NITAGs into the process, or that the unique pathway for vaccine approval has yet to be fully considered. Although a specific reason is unknown, our main goal was to address this need for incorporating vaccine-specific expertise in the EU HTAR.

Little detail is provided on the methodology of the literature review, for example, the search string is not presented, and neither are inclusion and exclusion criteria for the review. In the results, no information on number and types of reviewed studies is provided, and there is no systematic data extraction. The methodology of the case studies is similarly unclear. This puts to question the reproducibility of the study.  

In my assessment the paper is an editorial or opinion piece, rather than a research paper. I would suggest the authors add more detail on their research methods, and their findings, in a systematic way. Otherwise, they may want to consider rewriting it more squarely as an opinion piece.  

Thank you for addressing this point. We acknowledge that our initial methodology section lacked details. To address this, we have now included our search terms to the methodology section, along with the key inclusion criteria for our literature review. Specifically, we conducted a targeted literature review rather than a systematic one, focusing on publications discussing vaccine-specific HTA processes in the EU, the roles of NITAGs, and relevant regulatory frameworks. As is common practice in targeted reviews, we did not employ systematic data extraction or predefined inclusion/exclusion criteria but instead aimed to provide a comprehensive and relevant overview of the existing landscape.

Regarding the case studies, our primary source of information were the official websites of key regulatory and advisory bodies related to HTA. In instances where information gaps or uncertainties arose, we directly contacted these institutions for clarification. We recognize that this approach was not systematic and did not follow a predefined methodology. We now explicitly acknowledge this limitation in the revised manuscript.

Overall, we agree with the reviewers comment that our paper can be better presented as perspective piece supported by a literature review. Therefore, we updated our study design in the introduction (line 144), methodology (line 200-203), and discussion (line 421-423) to better reflect this.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

 Title:

Strengthening the EU HTA Regulation: Integrating NITAGs for Comprehensive Vaccine Assessments

-  Appropriate

Introduction:

1^st para presents a very strong, clear and relevant message. Vaccines are regulated as medicinal products, but are preventative measures delivered at a population level, to be effective. Access defined at member state level, vaccines require distinct framework and expertise.

2^nd para: NITAGs formed as a result of WHO Global Vaccine Action Plan, through the European Centre for Disease Prevention and Control (in 2018)

NITAG roles, activities, and outcomes vary across the fragmented European HTA frameworks. Leads to variations and discrepancies

3^rd para: relationship to HTA bodies, and how access is affected - demonstrates the importance of including NITAGs in the assessment of vaccines to improve HTA alignment.

4^th para: EU HTAR

Goes into the shortfalls of HTA processes for vaccines – this breaks the logical progression of the Introduction – and I do not think is appropriate here. Appropriate to combine with next paragraph. The HTAR aims to bring together the member state actions – this could even out the variations and differences in levels of expertise with regard to vaccines?

Yet, in paras 7 and 7, no specific methods under consideration in the implementation acts, with vaccines to be included in 2030

Make clear that the 2028 evaluation is for the EU HTAR to date.

Lines 106 and 111 are really unclear

Surely the main point is that stakeholders want dialogue and discussion now and ongoing, particularly in relation to NITAGs?

Line 120: The aim of this study was to identify the gap that arises if NITAGs are not included in the EU HTAR – VERY NEGATIVE APPROACH, CAN IT BE TURNED AROUND TO ‘HOW THE EXPERTISE AND ACTIONS BY NITAGs CAN CONTRIBUTE

-          and to develop recommendations for involving NITAGs under the Regulation

This study contributes to this ongoing dialogue – from an industry perspective? (in collaboration with Vaccines Europe Market Access working group, EFPIA?)

Materials and methods

1.       The review focused on identifying relevant literature on the role of NITAGs, the EU HTAR, and vaccine-specific HTA

2.       Case study of 3 member states

Sentence beginning Line 151 – very unclear

What are the differences expected with HTAR?

Line 165: sentence long and it is not clear what is being said. The whole paragraph is unclear – and how it related to the aims of the study?

Results:

Line 176: As several steps of the EU HTAR overlap with the current vaccine market access pathway, it is important to ‘streamline’ the processes … - surely what you are asking is ‘how NITAGs, their knowledge and expertise’, can be used to build the processes AND expertise?

Line 180: ..EMA REGULATORY processes…

Line 182: EMA evaluation process – what is this?

Use of ‘shall be’ – with HTAR?

I do not think this level of detail is needed here

Line 188: last part of last sentence – not clear what the authors are trying to say

I am not sure this is a useful start to the Results section, and how it relates to the literature review, with all the detail given. More and very specific sub-headings may be useful

Role of NITAGs given the differences across member states:

Challenges and Opportunities under the HTAR – I would turn this around to 1. Opportunities, 2, challenges, including in Table 1!

Better to present in a positive, and supportive manner, for NITAGs and for open dialogue, with objective of improving access to vaccines and shortening timelines?

3.2. 3 member states that involve NITAGs but use different approaches – the question is how these approaches could be better aligned? 

Figures 2 to 4: not sure these add to any argument or discussion point. NITAG is not referred to in Figure 4.

3.3 Recommendations:

Line 340: here is a need to ‘improve’ how the EU HTAR will accurately evaluate vaccines – my understanding is that you want to be part of open discussion on processes that involve the knowledge and expertise held by NITAGs and others to develop effective HTAR processes (not just ‘improve’)

Not sure the order of recommendations is logical

-          Why wait until 2028 to discuss?

-          Line 347 – it is not just about training but rather in coming to a common understanding of what is required for vaccines

 Discussion:

 At present the starting paragraph is an odd/apparently random mixture of points

 Better to come from a position of strengths, and to provide more uniformity, build levels of expertise?

The point of 2028 being a logical DEADLINE to adjust the HTAR re vaccines has not been made clear early in the manuscript

Agree with ‘what is needed’ including other possible roles for NITAGs

Conclusion:

Line 439: - AND BROAD DISCUSSION AMONG THE VARIOUS STAKEHOLDERS?

Key message:

ABSTRACT, Conclusions: Integrating vaccines into the EU HTAR and involving NITAGs can streamline assessments, reduce duplication, and improve alignment between European and national processes. Strategic

actions, including capacity building and collaborations between NITAGs, are critical for a successful implementation.

Keywords: Health Technology Assessment; NITAGs; EU HTAR; Joint Clinical Assessment; Vaccines; ACCESS, PUBLIC HEALTH?

Author Response

Response to Reviewers

Manuscript title: Strengthening the EU HTA Regulation: Integrating NITAGs for Comprehensive Vaccine Assessments

Reviewer 2

Title:

Strengthening the EU HTA Regulation: Integrating NITAGs for Comprehensive Vaccine Assessments

-  Appropriate

Introduction:

1^st para presents a very strong, clear and relevant message. Vaccines are regulated as medicinal products, but are preventative measures delivered at a population level, to be effective. Access defined at member state level, vaccines require distinct framework and expertise.

2^nd para: NITAGs formed as a result of WHO Global Vaccine Action Plan, through the European Centre for Disease Prevention and Control (in 2018)

NITAG roles, activities, and outcomes vary across the fragmented European HTA frameworks. Leads to variations and discrepancies

3^rd para: relationship to HTA bodies, and how access is affected - demonstrates the importance of including NITAGs in the assessment of vaccines to improve HTA alignment.

4^th para: EU HTAR

Goes into the shortfalls of HTA processes for vaccines – this breaks the logical progression of the Introduction – and I do not think is appropriate here. Appropriate to combine with next paragraph. The HTAR aims to bring together the member state actions – this could even out the variations and differences in levels of expertise with regard to vaccines?

Thank you for addressing this point. We agree that this paragraph was breaking the flow of the introduction here, and incorporated the reviewer’s suggestion to combine this with the next paragraph (lines 90-93). This indeed improves readability and flow of the introduction.

Yet, in paras 7 and 7, no specific methods under consideration in the implementation acts, with vaccines to be included in 2030

Make clear that the 2028 evaluation is for the EU HTAR to date.

Thank you for your feedback. We have clarified this point (line 128-130) have emphasized the reasoning behind using that evaluation moment.

Lines 106 and 111 are really unclear

Thank you for pointing out this unclarity, we updated these lines now to make them more readable.

Surely the main point is that stakeholders want dialogue and discussion now and ongoing, particularly in relation to NITAGs?

Ensuring dialogue and discussion among stakeholders, particularly regarding the role of NITAGs, is indeed a key objective of this paper. We fully acknowledge the importance of this point and have incorporated your feedback to further emphasize this throughout the introduction and discussion.

Line 120: The aim of this study was to identify the gap that arises if NITAGs are not included in the EU HTAR – VERY NEGATIVE APPROACH, CAN IT BE TURNED AROUND TO ‘HOW THE EXPERTISE AND ACTIONS BY NITAGs CAN CONTRIBUTE

-          and to develop recommendations for involving NITAGs under the Regulation

Thank you for raising this point. We aimed to not have a negative standpoint to the current EU HTAR but rather highlight the potential opportunities there are for including NITAGs and incorporating the specific characteristics of vaccines in the Regulation. However, we acknowledge that certain parts of the manuscript could benefit from clearer language on this point. To address this, we have specifically rephrased line 143 and have also revised the introduction, results, and discussion sections to ensure a more positive and constructive tone throughout.

This study contributes to this ongoing dialogue – from an industry perspective? (in collaboration with Vaccines Europe Market Access working group, EFPIA?)

We appreciate this point and would like to clarify that while this paper was written in collaboration with the Vaccines Europe Market Access working group, a specialized vaccines group within EFPIA, it is not solely framed from an industry perspective. Our research builds on several literature sources, and the first two sections of our results aim to present these from a neutral standpoint. The third section, discussing the recommendations, does indeed reflect an industry perspective, as these are developed in collaboration with Vaccines Europe. Recognizing the importance of a broader dialogue, we emphasize in our discussion that next steps would involve engaging with relevant stakeholders to further refine these recommendations and explore their roles in the evolving EU HTAR landscape, to ensure that not only an industry perspective is captured, but also the views and priorities of policymakers, public health authorities, HTA bodies, and other key stakeholders.

Materials and methods

1. The review focused on identifying relevant literature on the role of NITAGs, the EU HTAR, and vaccine-specific HTA
2. Case study of 3 member states

Sentence beginning Line 151 – very unclear

What are the differences expected with HTAR?

Thank you for pointing this out. We have restructured and simplified this sentence to improve clarity and readability. We did indeed mean to examine the differences expected with the HTAR.  

Line 165: sentence long and it is not clear what is being said. The whole paragraph is unclear – and how it related to the aims of the study?

Thank you for this feedback. We have revised this whole paragraph to better convey our message   

Results:

Line 176: As several steps of the EU HTAR overlap with the current vaccine market access pathway, it is important to ‘streamline’ the processes … - surely what you are asking is ‘how NITAGs, their knowledge and expertise’, can be used to build the processes AND expertise?

Thank you for your insightful comment. We have revised the sentence to better clarify the role of NITAGs, their knowledge, and expertise in building and enhancing the processes under the EU HTAR. The revised version more explicitly emphasizes how NITAGs can contribute to streamlining vaccine assessments by integrating their specialized knowledge into the broader framework, ensuring that vaccine-specific characteristics are fully considered and all relevant stakeholders are involved in joint HTA activities.

Line 180: ..EMA REGULATORY processes…

Line 182: EMA evaluation process – what is this?

Thank you for raising this issue. We have rephrased this term to the EMA marketing authorization procedure to clarify.

I do not think this level of detail is needed here

We appreciate this feedback and have revised the paragraph, by taking out the specific milestones, as these are also included in the timelines in figures 2-4.

Line 188: last part of last sentence – not clear what the authors are trying to say

Thank you for your feedback. We recognize that the last part of this sentence in was unclear and may have hindered the reader’s understanding. To address this, we have reworded the sentence to ensure clarity and precision, more clearly explaining the point we are trying to make: namely the fact that the impact of the EU HTAR on national timelines is still very uncertain due to the variety in the processes.  

I am not sure this is a useful start to the Results section, and how it relates to the literature review, with all the detail given. More and very specific sub-headings may be useful

Thank you for your valuable feedback. To address this, we have clarified how the findings from the literature review have contributed to the development of the results, particularly in relation to identifying key themes and gaps.

Role of NITAGs given the differences across member states:

Challenges and Opportunities under the HTAR – I would turn this around to 1. Opportunities, 2, challenges, including in Table 1!

Better to present in a positive, and supportive manner, for NITAGs and for open dialogue, with objective of improving access to vaccines and shortening timelines?

Thank you for this valuable suggestion. We have incorporated this feedback by restructuring the section titles, text, and Table 1 to first highlight the opportunities under the HTAR, followed by the challenges. This reorganization aligns with our broader effort to instill a more positive tone throughout the manuscript. As previously mentioned, we have revised the introduction, results, and discussion sections to emphasize the potential improvements that can be achieved through NITAG involvement, rather than focusing primarily on the challenges arising from their exclusion. These changes ensure a more constructive and forward-looking perspective on how NITAGs can contribute to strengthening vaccine assessment within the EU HTAR framework.

3.2. 3 member states that involve NITAGs but use different approaches – the question is how these approaches could be better aligned? 

Thank you for this insightful comment. We acknowledge that the three member states in our case study involve NITAGs but use different approaches in their vaccine assessments. In response to your question, we have added a section in the discussion, discussing how these different approaches could be better aligned. Specifically, we highlight the potential benefits of greater collaboration and standardization of processes between NITAGs and national HTA bodies, ensuring that the strengths of each country's approach can be shared and adapted to create a more cohesive and efficient EU-wide framework for vaccine assessments under the HTAR.

3.3 Recommendations:

Line 340: here is a need to ‘improve’ how the EU HTAR will accurately evaluate vaccines – my understanding is that you want to be part of open discussion on processes that involve the knowledge and expertise held by NITAGs and others to develop effective HTAR processes (not just ‘improve’)

You are absolutely right, and we appreciate your observation. In response to this feedback, we have clarified this aspect in the revised manuscript to highlight the collaborative nature of the process and the importance of co-developing these processes with relevant stakeholders. We hope this better reflects the intent of fostering open discussions and mutual collaboration to ensure that the EU HTAR can effectively assess vaccines and improve access to vaccination across MS.

Not sure the order of recommendations is logical

Thank you for your comment. We understand your concern regarding the order of the recommendations. To clarify, the recommendations were not presented in a prioritized sequence, but we recognize that this may have caused some confusion. In response, we have added a note to the recommendations section and throughout the discussion to explicitly indicate that the recommendations are not yet prioritized.

Additionally, we have revised the discussion to emphasize that these recommendations are potential strategies, and their prioritization, feasibility, and timeline for implementation should be determined in collaboration with key stakeholders. By engaging with these stakeholders, we aim to ensure that the recommendations align with existing frameworks, address practical challenges, and consider the varying needs of EU Member States. We also note that further discussions and cross-sector collaborations will be essential to refine these recommendations, prioritize them, and develop a clear plan for their integration into the evolving EU HTA landscape.

We hope this revision helps to clarify the intent behind the recommendations and the process of their future development.

-          Why wait until 2028 to discuss?

Thank you for raising this issue. We have clarified this point in the introduction (line 128-130) to emphasize that the 2028 evaluation moment is a logical deadline because of the fact that it is not possible to change the implemented legislation at this point in time.  

-          Line 347 – it is not just about training but rather in coming to a common understanding of what is required for vaccines

Thank you for your feedback. We understand that the focus of this recommendation should be about building the common understanding, not so much on providing training specifically, as this is only the tool to reach the goal. To reflect this, we have rephrased the sentence.

 Discussion:

 At present the starting paragraph is an odd/apparently random mixture of points

Thank you for pointing this out. We have revised this part of the discussion, to create a better, more understandable flow in the story.

 Better to come from a position of strengths, and to provide more uniformity, build levels of expertise?

Thank you for your suggestion. We have revised the discussion to focus more on the strengths and opportunities, rather than the weaknesses and challenges. Additionally, we have put more emphasis on the alignment between the different MS and the importance of uniformity.

The point of 2028 being a logical DEADLINE to adjust the HTAR re vaccines has not been made clear early in the manuscript

Like mentioned above, we have clarified this point in the introduction (line 128-130) to emphasize that the 2028 evaluation moment is a logical deadline because of the fact that it is not possible to change the implemented legislation at this point in time.  

Agree with ‘what is needed’ including other possible roles for NITAGs

Conclusion:

Line 439: - AND BROAD DISCUSSION AMONG THE VARIOUS STAKEHOLDERS?

Thank you for your valuable comment. We have incorporated the suggestion to emphasize the importance of fostering broad discussion among various stakeholders in the revised paragraph. By including this point, we indeed aim to highlight the need for ongoing dialogue and collaboration among all relevant parties.

Key message:

ABSTRACT, Conclusions: Integrating vaccines into the EU HTAR and involving NITAGs can streamline assessments, reduce duplication, and improve alignment between European and national processes. Strategic

actions, including capacity building and collaborations between NITAGs, are critical for a successful implementation.

Keywords: Health Technology Assessment; NITAGs; EU HTAR; Joint Clinical Assessment; Vaccines; ACCESS, PUBLIC HEALTH?

Author Response File: Author Response.pdf