Further details of the HTA appraisal/reimbursement processes for the majority of EU and EEA member states have been documented by IMPACT HTA and can be viewed here:

https://www.impact-hta.eu/country-vignettes

In Europe, all medicines must obtain a marketing authorisation from a regulatory authority before they can be marketed and made available to patients. National regulatory authorities are responsible for the evaluation and authorisation of medicines to be marketed solely within that country’s jurisdiction. A full list of national regulatory agencies in the European Economic Area can be found here:

https://www.ema.europa.eu/en/partners-networks/eu-partners/eu-member-states/national-competent-authorities-human

The European Medicines Agency (EMA) is responsible for the scientific evaluation of single marketing authorisation applications for medicines to be marketed across the EU and the European Economic Area.

In 2004, the European Commission and Council of Ministers recognised the need for a sustainable European network on HTA. Subsequently, EUnetHTA (EUnetHTA Project 2006-08;  EUnetHTA Collaboration 2009; EUnetHTA Joint Action 2010-12; EUnetHTA Joint Action 2 2012-15 and EUnetHTA Joint Action 3 2016-20) was established to create an effective and sustainable network for HTA across Europe, through collaboration between European HTA organisations. As part of its activities, EUnetHTA produced methodological guidelines, undertook joint relative effectiveness assessments, and facilitated early dialogues on pharmaceutical products and medical devices. EUnetHTA Joint Action 3 ended on 31st May 2021. However, in June 2021, the European Parliament and Council of the European Union reached an agreement on a legislative proposal for joint work on HTA, including joint clinical assessments and joint scientific consultations on health technologies. 

On 17 September 2021, the European Health and Digital Executive Agency (HaDEA) signed the Service Contract for the Provision of Joint Health Technology Assessment (HTA) Work Supporting the Continuation of EU Cooperation on HTA known as EUnetHTA21. The contract will run for 24 months, and until 16 September 2023. The EU HTA Regulation that came into effect in January 2022 will serve as a basis for all EUnetHTA 21 deliverables and the deliverables will take into account the past EUnetHTA Joint Action experiences. EUnetHTA 21 will support the development of guidance documents to be adopted by the HTA Coordination Group and/or drafting of implementing legislation by the European Commission, thus facilitating the subsequent implementation of the HTA regulation. The EUnetHTA 21 joint consortium is led by ZIN (The Netherlands) and includes the following HTA agencies: AEMPS (Spain), AIFA (Italy), AIHTA (Austria), G-BA (Germany), HAS (France), Infarmed (Portugal), IQWIG (Germany), KCE (Belgium), NCPE (Ireland), NIPN (Hungary), NOMA (Norway) and TLV (Sweden).

https://www.eunethta.eu/eunethta-21/

FINOSE is a Nordic collaborative HTA network between Finland (Fimea), Norway (NoMA) and Sweden (TLV). It was established in 2018 to perform joint HTA assessments for medicines which include both relative clinical and health economic assessment. Further details on the initiative and the joint assessment process can be found here:

https://www.tlv.se/in-english/international-collaboration/finose---a-nordic-cooperation.html

https://www.fimea.fi/web/en/development/therapeutic_and_economic_value_of_medicines/nordic-collaboration-finose-

• Scientific guidelines | European Medicines Agency (europa.eu)

• Clinical investigation of medicines for the treatment of Alzheimer's disease

• Clinical investigation of medicinal products in the treatment of Parkinson's disease

• Clinical investigation of medicinal products for the treatment of amyotrophic lateral sclerosis

• Clinical investigation of medicinal products for the treatment of multiple sclerosis

• Questions and answers: Qualification of digital technology-based methodologies to support approval of medicinal products

• Guideline on registry-based studies

• EMA Opinions and letters of support on the qualification of novel methodologies for medicine development

• Qualification opinion on Multiple sclerosis clinical outcome assessment (MSCOA)

• Qualification opinion on stride velocity 95th centile as a secondary endpoint in Duchenne Muscular Dystrophy measured by a valid and suitable wearable device

• Qualification opinion on dopamine transporter imaging as an enrichment biomarker for Parkinson’s disease clinical trials in patients with early Parkinsonian symptoms

• Qualification opinion of a novel data driven model of disease progression and trial evaluation in mild and moderate Alzheimer’s disease

• Qualification opinion of Alzheimer’s disease novel methodologies/biomarkers for the use of CSF AB 1-42 and t-tau and/or PET-amyloid imaging (positive/negative) as biomarkers for enrichment, for use in regulatory clinical trials in mild and moderate Alzheimer’s disease

• Qualification opinion of low hippocampal volume (atrophy) by MRI for use in clinical trials for regulatory purpose - in pre-dementia stage of Alzheimer’s disease

• Qualification opinion of novel methodologies in the predementia stage of Alzheimer’s disease: cerebro-spinal fluid related biomarkers for drugs affecting amyloid burden

• Qualification Opinion of Alzheimer’s Disease Novel Methodologies/biomarkers for BMS-708163

• Letter of support for Mobilise-D digital mobility outcomes as monitoring biomarkers

• Letter of support for Mobilise-D digital mobility outcomes as monitoring biomarkers – Follow-up

• Letter of support for molecular imaging of the dopamine transporter biomarker as an enrichment biomarker for clinical trials for early Parkinson's disease

EUnetHTA has produced a number of methodological guidelines on the key challenges for HTA assessors in the relative effectiveness assessments of pharmaceuticals or non-pharmaceutical health technologies.There will be further methodological guidelines delivered as part of EUnetHTA21.

• Health Technology Assessment International (HTAi)

• International Society for Pharmacoeconomics and Outcomes Research (ISPOR)

• International Network of Agencies for Health Technology Assessment (INAHTA)

• GetReal Institute

• International HTA database

• HTA Glossary

• Real-world evidence (RWE) Navigator

• Toolkit for the identification, selection and measurement of outcomes including in real-world settings

• EUPATI Toolbox

• FDA Drug Development Tools

• PARADIGM Patient Engagement Toolbox

• Accelerated Development of Appropriate Patient Therapies: a Sustainable, Multi-stakeholder Approach from Research to Treatment-outcomes (ADAPT SMART)

• European Patients' Academy on Therapeutic Innovation (EUPATI)

• Next Generation Heath Technology Assessment (HTx)

• Improved methods and actionable tools for enhancing HTA (IMPACT HTA)

• Patients Active in Research and Dialogues for an Improved Generation of Medicines (PARADIGM)

• Patient Preferences in benefit risk assessments during the drug life cycle (PREFER)

• Pushing the boundaries of Cost and Outcome analysis of Medical Technologies (COMED)

• Strengthening Regulatory Science (STARS)

• Center of excellence – remote decentralised clinical trials (Trials@Home)

In the early stages of research, many projects have questions and issues that they are interested in exploring with regulatory agencies. The EMA’s Innovation Taskforce (ITF) provides a platform for early discussions that can help to shape the way that research is planned and can inform the EMA of emerging innovative therapies and technologies.

This case study focuses on a research project whose goal is to develop clinically meaningful digital endpoints for functional decline in early Alzheimer’s disease. The project was in the early stages of planning the design of their study and wanted to engage early with health authorities to ensure the study design met regulatory expectations. The ITF was chosen as the most appropriate mechanism for engagement as it would allow the project to explore more high level, conceptual questions about exploratory, novel techniques without the need to share data which would be required for other procedures (e.g. qualification of novel methodologies). 

Preparation for the meeting was relatively straightforward and light touch and involved the preparation of a presentation about the project. However, planning the presentation required consortium discussions and agreement on how to present the project, the key issues they wanted to highlight, and the questions that they wanted to ask. The project also had to consider who would represent them at the meeting, balancing the practicalities of availability of representatives (taking into account the different time zones of partners) with ensuring they had a good mix of people with a good working knowledge of the project as well as more senior, strategic representatives. 

The ITF meeting itself provided the opportunity to engage with an expert panel in an informal, two-way dialogue. As a result of the meeting, the project changed its strategy for regulatory engagement. It had originally planned to seek a qualification opinion but following ITF feedback determined that this was too ambitious within the project timelines. The project is now planning to seek qualification advice from the EMA and, in parallel, HTA advice, at the end of the project. The intention is to use the qualification advice to inform the development of a longitudinal study which could potentially result in a qualification opinion. The team is also planning to engage with HTA bodies in parallel. They may also seek interactions with the FDA, following recommendations resulting from the IMI mid-term review.

Overall, the project felt that the ITF offered a useful means of engaging with a diverse panel of experts, enabling them to get some fresh ideas and options that they had not considered as a consortium. For more detailed feedback the team is planning for a qualification advice. 

Before undertaking this, or any other procedure, the project recommends agreeing as a consortium what the project’s ultimate aim is and what outputs the consortium would like to see as a result of the procedure. It is also important to embed regulatory engagement into the project structures and strategy and to provide regular feedback to consortium members, ensuring that they understand why it is relevant to their work in the project.

For researchers developing innovative methods or drug development tools, scientific advice is available through the EMA’s qualification procedure. This case study focuses on a research project with an objective to establish validated and accepted digital mobility outcomes, derived from wearable sensors, that can be used as appropriate biomarkers for clinical benefit in clinical trials of new pharmaceutical products. To achieve their objective, the project chose to seek qualification advice from the EMA using a staged approach. So far, the project has sought two rounds of qualification advice and received two letters of support which publicly endorse the project’s approach.

In preparation for the procedure, the project was required to develop a briefing book which was submitted to the EMA and provided the basis for discussions. Having pharmaceutical companies with vast experience of regulatory procedures on the consortia was an advantage as it helped them to navigate the formal processes. However, building a compelling and robust argument was particularly challenging. The consortium created a Qualification Task Force (QTF), which included all partners who were willing to actively contribute to the preparation of the briefing book, and a Qualification Interest Group, which included all those in the consortium who wanted to be kept informed about this work.  Once the QTF was established, the first request for qualification advice was submitted after six months.  The process included an informal face to face preparatory meeting with an EMA officer, and a formal meeting with the Scientific Advisory Working Party of EMA.

The procedure resulted in a change to plans to undertake qualitative research to support the need for monitoring real world mobility which had originally been discounted as an idea. The project is now preparing a submission to the FDA DDT program, including plans for qualitative research following advice from the EMA. It is also hoped that the project will have sufficient data to pursue a qualification opinion before the end of the project.

The key learning from undergoing this process was the need to communicate a clear logical reasoning on the constructs and the hypotheses, and how they were going to test them. In dealing with complex problems, such as these, it takes time and a lot of work to do this effectively.

This case study focuses on a research project that sought scientific advice before starting critical aspects of the project. They undertook two scientific advice procedures, as well as a consultation with the EMA’s Clinical Trials Facilitation Group. The purpose of these interactions included advice on the development of a master protocol, the approach being taken to establish a proof-of-concept (PoC) platform for use in drug development, the use of the PoC trial as a pivotal study for regulatory purposes, and plans for the statistical analysis of data from a longitudinal study.

In preparation for these interactions, the project team spent considerable time and effort developing a briefing document and writing specific questions. For the scientific advice procedures the project team received clear and detailed written answers to the scientific advice questions, and written minutes from the meeting with the Clinical Trials Facilitation Group. 

Overall, the project received useful advice from both scientific advice and the Clinical Trials Facilitation Group. This included clear advice from the Clinical Trials Facilitation Group on what to do if submitting to the EMA, and scientific advice on exploratory endpoints and analysis. However, whilst useful, the advice received did not result in any changes to the master protocol or to the clinical or scientific outputs. One reflection was that it isn’t always clear which procedure to follow. The project also felt that it would’ve been useful to have engaged with HTA bodies on how they would value exploratory endpoints in their assessments, even if it was just for educational/awareness raising about the work they were leading. 

A key learning from the procedures was that, as a consortium, it is helpful to identify one partner that will take responsibility and ownership for driving the process forward. In addition, whilst completing the briefing books was straightforward, it can take considerable time to do. This particular project found that not all partners had the same level of understanding of the purpose of the procedures and the questions that were appropriate to ask. It therefore took time to ensure that all partners were aligned on the purpose of the procedure and to develop clear questions that would be asked, taking into account the different needs and expectations of project partners. 

The project found that their informal interactions with the EMA were extremely useful in guiding their thinking and tried to enlist the EMA as a consortium member, although were unsuccessful. As a compound agnostic project, they felt that taking an informal partnership approach would’ve been better than the formal scientific advice route they ultimately followed. One way to facilitate this would be to require all future projects to include a regulatory representative on the consortium in an advisory capacity.

One way to ensure that the design of research studies meets the needs of both regulatory and HTA bodies is to seek parallel scientific advice. This case study focuses on the advice provided to a project from the EMA and one HTA body on the design of a diagnostic study and the choice of efficacy measures and health outcomes to effectively evaluate impact. 

For the scientific advice procedure, the project was required to develop a briefing document, including the specific scientific questions relating to the design of the study and their proposed responses. The document took around 3 months to prepare. After submission, a face-to-face meeting was held with the EMA and NICE to discuss the questions and then both agencies provided separate written responses to the questions.

Overall, the advice received from both agencies helped to shape the development of the study protocol. For example, the EMA provided valuable guidance on study designs and endpoints which resulted in a change to the primary endpoint of the study. Additionally, secondary endpoints relating to resource utilisation were added as a result of the HTA advice.

The project benefited from the parallel procedure and recognised the value in seeking early advice in helping to shape the design of the study. However, there were also some challenges and lessons learned. Firstly, the preparation for the procedure was very time consuming. As a consortium, time was needed to gain agreement from all partners on what the questions would be and the position that they want to take on them. Sufficient time therefore needs to be factored into any project planning. 

As a parallel procedure, all HTA bodies in Europe were invited to participate but only one body accepted and participated in the procedure, and a further one HTA body observed the meeting. From a HTA perspective it would have been better if they could have received advice from multiple HTA bodies at the same time. In addition, whilst some of the advice provided by the EMA and HTA body was similar, there was also some contrary advice relating to the design of the study. For example, EMA advice for a study demonstrating the impact of initial diagnosis compared to HTA advice for a complete pathway of care study. These differences reflected the different requirements of the agencies. The project had to determine which advice was most relevant and achievable to implement within the project timelines and resources.

Following the initial scientific advice procedure, the project sought further scientific advice from the EMA later in the project on more conceptual questions relating to biomarkers. As well as gaining feedback it also gave them the opportunity to introduce new concepts to the EMA.

Types of new research which might require interactions with regulatory and/or HTA bodies:

• New analytical methods

• New biomarkers

• New drug targets

• New non-clinical models

• New modelling & simulation tools

• New clinical tools & methodologies

• New approaches for clinical trials

• New disease definitions

• New clinical endpoints

• New clinical outcome assessments

The EMA’s Innovation Task Force (ITF) provides an opportunity for academics, researchers, and SMEs to meet with EMA staff and scientific committee members for informal discussions about their research activities. The discussions can focus on scientific, legal and regulatory aspects relating to the development of new medicines or new scientific approaches that might be used during drug development or approval (e.g. biomarkers, modelling and simulation, or novel clinical trial methodology). The aim of ITF meetings is to facilitate discussions and to identify what other, more formal regulatory procedures might be appropriate for the technology under development.

https://www.ema.europa.eu/en/human-regulatory/research-development/innovation-medicines#ema's-innovation-task-force-(itf)-section

The PRIority MEdicines scheme (PRIME) designation is intended for medicines that meet certain criteria, such as addressing unmet medical needs and possibly offering substantial benefits to patients. The manufacturers of drugs that are accepted into the PRIME scheme receive early support from the EMA. This can include discussions with the EMA on data collection plans to facilitate the earliest appropriate patient access. Applicants from SMEs and the academic sector are able to apply for PRIME at an earlier stage of development and may also request a fee waiver for scientific advice. Drugs that have a PRIME designation also receive accelerated assessment. 

https://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicines

EU legislation includes several provisions to speed up access to new medicines. These include:

• Accelerated Assessment: The EMA offers an accelerated assessment process with shorter assessment times for drugs that meet certain criteria, such as those that are a major interest for public health or aimed at addressing unmet medical needs. The assessment time for marketing authorisation is reduced from 210 days to 150 days or less for accelerated assessments. If accelerated assessment is being considered, developers are advised to request a pre-submission meeting with the EMA 6-7 months before submission to prepare for the evaluation.

https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/accelerated-assessment 

• Conditional marketing authorisation (CMA): CMA is a tool to enable approval of a medicine that addresses an unmet medical need based on less comprehensive clinical data than is usually required. To be eligible, the benefit of the medicine’s immediate availability must outweigh the risks of its approval. As part of the conditional approval, developers are required to gather more comprehensive data (such as ongoing or new studies) within an agreed timeframe. If CMA is being considered, developers are advised to discuss with the EMA at the earliest opportunity during a medicine’s development, through scientific advice/protocol assistance.

https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/conditional-marketing-authorisation

SMEs are defined by the EMA as pharmaceutical companies that have fewer than 250 employees and that have an annual turnover of <€50m. The EMA has a dedicated team which provides administrative, regulatory and financial support to SMEs. This includes fee reductions for most regulatory procedures such as scientific advice and marketing authorisation applications.

https://www.ema.europa.eu/en/human-regulatory/overview/supporting-smes

The EMA offers a number of regulatory and scientific support tools that are applicable to medicine developers from the academic sector (e.g. Innovation Task Force, Qualification of novel methodologies, Scientific advice & Protocol assistance). Academics are able to request fee waivers for scientific advice as part of the PRIME scheme as well as receiving free protocol assistance for orphan medicines. To support academic researchers through the regulatory framework, there is a dedicated point of contact at the EMA (Academia@ema.europa.eu). 

https://www.ema.europa.eu/en/documents/leaflet/ema-tools-available-medicines-developers-academic-sector_en.pdf

Scientific Advice enables researchers and drug developers to ask questions about new methods for drug development, clinical trial designs and evidence development plans. The aim of scientific advice is to ensure that evidence generation plans can support marketing authorisation applications and HTA submissions for new drugs.

The EMA provides scientific advice on the best methods for generating evidence to demonstrate the quality, safety and efficacy of a medicine. Advice is provided by responding to specific questions from the manufacturer on aspects including quality, trial design and data analysis. Manufacturers can request scientific advice at any stage of a drug’s development and regardless of whether it is eligible for authorisation under the centralised procedure offered by the EMA.

https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-advice-protocol-assistance

Protocol assistance is a specific type of scientific advice provided by the EMA for manufacturers developing designated orphan drugs for rare disease.

https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-advice-protocol-assistance

The EMA offers scientific advice to developers and researchers on the development of new methods and tools (e.g. new biomarkers, disease models, etc) for use in drug research and development. Advice is available to pharmaceutical companies, research consortia, networks, or public-private partnerships. The process results in either a ‘qualification opinion’ or ‘qualification advice’:  

• ‘Qualification opinion’ on the acceptability of a proposed new method/tool, based on the assessment of protocols, study reports and supportive data. All qualification opinions are published on the EMA website.

• ‘Qualification Advice’ on draft protocols and development plans relating to a proposed method/tool, based on the evaluation of scientific rationale and preliminary data. Qualification advice is confidential, however, the EMA may propose a publicly available letter of support for methodologies which demonstrate potential but are not yet at the stage of qualification.

https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-advice-protocol-assistance/qualification-novel-methodologies-medicine-development-0

Developers can choose to request scientific advice on the scientific and regulatory aspects relating to the development of a medicine from an individual national regulatory agency perspective.

Some examples of national regulatory agencies that provide scientific advice include: 

• Belgium – Federal Agency for Medicines and Health Products (famhp)

• Finland – The Finnish Medicines Agency (Fimea)

• Denmark – Danish Medicine Agency

• Germany – Federal Institute for Drugs and Medical Devices (BfArM)

• Italy – Italian Medicines Agency (AIFA)

• Norway – Norwegian Medicines Agency (NoMA)

• Portugal – National Authority of Medicines and Health Products (infarmed)

• Sweden – Swedish Medical Products Agency

• United Kingdom – Medicines & Healthcare products Regulatory Agency (MHRA)

Further details of all national regulatory agencies in the European Economic Area can be found here: 

https://www.ema.europa.eu/en/partners-networks/eu-partners/eu-member-states/national-competent-authorities-human

The EMA and FDA (US regulatory agency) offer parallel scientific advice and protocol assistance. This enables developers to receive advice on particular scientific issues based on the requirements and perspectives of both regulatory agencies. 

https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-advice-protocol-assistance#parallel-scientific-advice-with-the-united-states-section

The EMA and EUnetHTA 21 will collaborate to provide parallel joint scientific consultations to manufacturers on the evidence requirements for marketing authorisation,health technology assessment and reimbursement relating to their drug development plans. This builds on previous initiatives and pilots led by the EMA, EUnetHTA and the European Commission. 

https://www.eunethta.eu/jointhtawork/parallel-consultation/

https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-advice-protocol-assistance/parallel-consultation-regulators-health-technology-assessment-bodies

Developers can request joint advice from a national regulatory agency and HTA body. Examples of countries that offer joint national scientific advice include:

• The Medicines Evaluation Board (MEB) and Zorginstituut Nederland (ZiN) (The Netherlands)

• Medicines and Healthcare products Regulatory Agency (MHRA) and NICE (UK)

• BfArM and the Federal Joint Committee (G-BA) (Germany)

A number of HTA bodies offer scientific advice procedures, providing manufacturers with feedback on the country specific clinical (e.g. comparator choice relevant to the national healthcare system) and economic HTA evidence requirements. Advice is available in a number of countries (England (NICE), Germany (G-BA), France (HAS) and Sweden (TLV)) and varies in terms of scope, timescales and costs.

Regulatory and HTA bodies may require additional evidence following the approval of a drug. From a regulatory perspective, post-authorisation safety studies may be required as part of the authorisation of a medicine. Evidence may also be requested post-launch by national HTA bodies, for example, as part of a market access agreement. Developers may also voluntarily choose to undertake additional studies to support further development of approved products. 

To support post-launch evidence generation plans, developers may wish to seek scientific advice from European and national regulatory bodies and/or HTA bodies. Further details of the support available from the EMA are available here:

https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-advice-protocol-assistance#scientific-advice-on-post-authorisation-safety-studies-(pass)-section

The process/methods for HTA vary across different bodies. Further guidance is published on the websites of individual HTA agencies (e.g. Fimea (Finland), G-BA (Germany), HAS (France), NCPE (Ireland), NICE (England), NoMA (Norway)).  During the assessment process, there may be opportunities to engage with the relevant HTA body regarding any questions or issues relating to the evidence submission. For example, the Norwegian Medicines Agency (NoMA) offers pre-meetings to developers in relation to the submission of documentation for assessment. Developers can request preliminary discussions with the Zorginstituut (The Netherlands) for advice on the data to include in the submission dossier. NICE (England) offers developers the opportunity to discuss key issues during the 60‑day submission preparation stage of the appraisal. The NCPE (Ireland) also holds pre-submission meetings with manufacturers to provide support prior to finalising submission documentation.

Developers should consider informal engagement with HTA bodies when developing a market access strategy, particularly around understanding the value proposition of new technologies being developed. For example, the NICE Office for Market Access (OMA) facilitates engagement meetings between manufacturers and relevant healthcare system stakeholders to support market access planning by helping them to understand the changing healthcare landscape and identifying the right route to NHS access.