EU HTA Regulation: Medicine Developers Countdown to Jan 2025

The EU (European Union) Health Technology Assessment Regulation (HTAR) (EU) 2021/2282 will come into force from January 2025, creating a harmonised clinical evaluation of health technologies across member states (MSs) with the ultimate aim to improve equal access to medicines across Europe. Value assessment of new technologies remains with national bodies, but the coordinated clinical assessment in parallel with centralised marketing authorisation applications (MAA) will impact developers of medicinal products and devices (health technology developers) ways of working and distribution of resources.

The new framework is led by the Health Technology Assessment Coordination Group (HTACG) made up of representatives of all MSs and supported by the European Commission’s (EC) HTA secretariat. Following the release of the HTA Regulation in 2022, the supporting Implementing Acts and Guidance are mostly available for medicines, with guidance for devices following behind.

This article provides a detailed review for medicines developers of the procedures available from January 2025 and some key considerations for their preparation and planning.

HTA Regulation, New Procedures for 2025

The phased implementation of the health technology assessment regulation (HTAR) EU Regulation 2021/2282 begins on 12^th January 2025. From this date, marketing authorisation applications (MAAs) for medicinal products with a new active substance for which the therapeutic indication is the treatment of cancer and medicinal products that are advanced therapy medicinal products (ATMPs), as defined in the regulation (EC) No 1394/2007, will be in scope for Joint Clinical Assessments (JCAs). The JCAs will be facilitated by the EU HTA Coordination Group (HTACG) in parallel with  European Medicines Agency (EMA) review of the MAA. The JCA outcome will provide core clinical effectiveness data to national HTA bodies to begin reimbursement assessment at the vel.

2025 will also see the launch of the Joint Scientific Consultation (JSC) process. The JSC is a framework for developers to obtain scientific input on the information and evidence needs for a subsequent Joint Clinical Assessment (JCA) during the clinical development of a health technology. Similarly to EMA scientific advice, the JSC report is not binding but needs to be considered for the subsequent JCA by the medicine developer and EU HTA Coordination Group (HTACG).

Developers will need to contact the HTA secretariat at the European Commission (EC) and utilise a new IT platform in order to navigate the Joint Clinical Assessment (JCA) and Joint Scientific Consultation (JSC) procedures. The HTA secretariat will coordinate the involvement of patients, clinical experts and other relevant experts (‘individual experts’) in joint clinical assessments and joint scientific consultations as described in the HTA regulation. The format and timelines for communication with the HTA coordination group (HTACG) are becoming clear with the majority of key guidelines now available.

A crucial consideration for medicine developers submitting MAAs for new products starting from January 2025 is understanding what is already known and what remains uncertain.

Impact on Near-Term EU MAA Submissions – Joint Clinical Assessment (JCA)

For developers in the final stages of MAA preparation, a key factor will be the preparation of the Joint Clinical Assessment (JCA) dossier and planning for responding to EMA D120 questions at the same time. Looking step-by-step at the JCA procedure, what is available to developers and what will be issued or clarified before 12^th January?

Eligibility request & IT platform access – Developers of new oncology and ATMP products have to notify both HTA and EMA of the planned submission of their MAA. The EMA eligibility request for pre-submission activities now includes a section to indicate if the HTA Regulation is applicable and asks applicant to send the form to the HTA secretariat in parallel. Developers are also encouraged to inform the HTA secretariat of their intention to submit an MAA that is in scope of the HTAR via email. Applicants will then receive access to a pre-submission workspace area (based on SharePoint) to provide the letter of intent to submit. The IT workspace allocates a procedure number, and this is used to track the JCA through subsequent steps.

• The HTA secretariat intends to provide guides to using the workspace and FAQs prior to January 2025

At MAA validation – The applicant provides the draft summary of product characteristics (SmPC) and Clinical Overview to the HTACG via the workspace to initiate the scoping exercise with all MSs. The workspace can provide notifications to parties involved in JCA review; however. it is not a messaging system so email to the HTA secretariat will be required during the procedure.

• Procedural guidance is available for JCA now – more practical information is expected prior to January 2025.

Receipt of the consolidated PICO request – for standard timetable MAAs the request is received 10 days after D120 List of questions from CHMP. The JCA Assessor and co-assessor draft the initial Population, Intervention, Comparator(s), Outcomes (PICO) and MSs review and add relevant points. The JCA subgroup for medicines will validate the request once drafted. The aim is to have an optimal number of PICOs but all PICOs requested by MSs can be included.

• Final PICO guidance is not published yet; however, this is expected to be based on previously released EUnetHTA PICO guidance and FAQs.

JCA dossier preparation – the applicant has 100 days from receipt of the scoping results to prepare the JCA dossier (for a standard timetable MAA with standard CHMP stop-clock, for extended stop-clocks the dossier is expected 45 days ahead of the CHMP opinion). Once submitted the HTA secretariat performs a completeness check and missing information can be requested from the developer to be submitted within 15 days. The implementing act includes provision for potential extension to the deadline for submission of the dossier in the case that the centralised procedure does not follow common timelines (i.e. extended stop-clock) and the decision to grant extension is made by the HTA secretariat in conjunction with the JCA assessors.

• All guidance on evidence synthesis and outcomes is already available.
• The Implementing act on exchange of information with the EMA is published.
• The structure of the JCA is captured in the implementing act Annex 1 along-side expectations for contents and data tables layout. Word template and filled in examples for data tables are expected prior to January 2025.
• JCA report will include guidance to MSs on the ‘degree of certainty’ of the relative effectiveness and relative safety, so detailed methodology is a key part of the dossier.

JCA report – The final JCA report must be issued on the day of the EC decision granting the MA. Given that there may be further data submitted to CHMP between D120 list of questions (LOQs) and the CHMP opinion it is envisioned that may be necessary to provide additional evidence to the HTACG, but this is limited to no later than 7 days after the CHMP opinion.

• The structure of the JCA report is captured in the implementing act Annex 2.

Publication of JCA report and dossier – As laid out in the HTA regulation (Article 30) both the JCA report and submitted dossier will be published following the procedure. Prior to publication the developer is given the opportunity to review. Developers have 7 days following receipt of the draft JCA report to advise of technical/factual inaccuracies and information considered to be confidential.  Developers must demonstrate the commercially sensitive nature of the information for it to be considered confidential.

• The JCA implementing act notes the commission will review the developer’s request for redaction of confidential information and inform of the decision to refuse or accept redaction. No further guidance is available on this process.

Updates to an existing JCA – Developers will have the opportunity to proactively submit new relevant information, data, analyses and other evidence to the HTACG – even if these were not specified in the initial JCA report. The HTACG will determine whether the update will be accepted into its annual work programme. Understanding of the types of new data or evidence that would support an update to the JCA will be important for the future.

Developers have a clearer picture of the process and expectations for the JCA and can access information from the HTA regulation itself, associated implementing acts and available guidelines. However, there is much learning to be had from the first JCA procedures and still some questions for the inevitable unplanned circumstances that may occur with any MAA review. Both EMA and HTACG are calling for increased planning from developers for MAA submission to support resource management at both organisations and to improve predictability of workload. This is reflected across several initiatives.

• The recent fees regulation includes fees for pre-submission activities and for delays in MAA submission date by more than 60 days to encourage increased accuracy (Fees payable to the European Medicines Agency | European Medicines Agency (EMA))
• Recent EMA measures which include more rigorous enforcement of existing guidance on the extension of stop-clocks from July 2024 which may result in not granting extensions for reasons of immature dossiers or issues that were foreseeable before submission (Improving efficiency of approval process for new medicines in the EU | European Medicines Agency (EMA)).
• A call for realistic rather than aspirational indication statements at the start of the MAA review will allow an efficient JCA process without the need to provide new evidence late in the process. Late changes to the indication will be problematic, the JCA report publication cannot be delayed beyond EC decision date, so if changes to the indication trigger the need to change PICOs or evidence there is little time to manage this. Communication of changes to the indication need to be notified to the HTACG urgently during review.

Impact for Mid-Term EU MAA Submissions – Joint Scientific Consultation (JSC)

For developers planning EU MAA submission for new ATMPs or oncology treatments in the next few years, the option for Joint Scientific Consultation (JSC) on evidence needed for the JCA should be considered. JSC offers consolidated feedback from MSs on clinical aspects of evidence generation, with discussion regarding potential PICO as its core purpose. JSC can also include advice on Post Licencing Evidence Generation (PLEG) if a study proposal is included, however, PLEG-only requests for JSC will not be granted. JSC can be sought alone or in parallel to regulatory scientific advice. For the latter, some information sharing is anticipated such as the EMA advice coordinator attending JSC meetings. However, the developer will receive separate outcome letters from CHMP and HTACG. There will be 2 specified time periods in 2025 in which JSCs can be requested. Overall, the JSC process is around 4.5 months once the draft briefing book is received.

• The consultation on the implementing act on JSC closed on 29 October and the final document is expected prior to January 2025.

The request template will be submitted and checked against the eligibility criteria, HTACG will have 15 days from the end of the request period to provide feedback on acceptance. If more than 10 requests are received selection criteria will be applied, this is to be defined in future guidance documents.

• Selection criteria, procedural guidance, request templates and briefing book templates are expected to be released in the near future.

Each JSC will include several phases and a discussion meeting with the developer, with relevant expert groups included. Once acceptance is communicated the developer will prepare the briefing book.  Following briefing book submission, the developer will receive a list of issues and provide a written response. A discussion meeting will be held, and the final outcome will be provided in writing following that meeting. The outcome is intended to provide the common position of MSs. Individual positions by specific MSs may be included in an Annex where further specifications are driven by national requirements.

Considerations for Medicines Developers

With the new framework of assessment and advice the implementation of the HTA regulation brings, there are many considerations for companies that may affect resourcing, governance and overall approach to product development. A key benefit of the new framework is to reduce volume of work for developers to submit multiple clinical dossiers in multiple EU MSs, as well as aiding in efficient resource use, and strengthen the quality of HTAs. However, there are potential new areas that may be challenging.

• Involvement of external experts – developers are recommended to review the implementing act for conflict-of-interest (COI) rules under the HTA regulation. Notably the act allows for exceptional involvement of experts with conflicts of interest in cases such as rare diseases where no individuals free from conflicts are available. This may be particularly important to developers of rare disease. All orphan products will be in scope for the JCA from 2028, but this is of relevance immediately as 16 of the 20 currently authorised ATMPs are in orphan conditions (and 5 of the 7 ATMP MAA under review are also orphan drugs).
• Many companies will have to manage two systems for HTA review: for older products or those not yet in scope the national HTA review; and the HTACG process for MAAs in scope of the JCA. Transition between old and new approaches will continue for decades, new applications for all products will be in scope in January 2030 but new indications for older products will continue to fall outside of JCA according to the current regulations.
• The search for and generation of evidence to address the results of scoping phase and PICO may be burdensome for smaller companies or teams. There will be challenges for both ATMP and Oncology assessments.
  • JCA assessment for ATMPs may pose additional challenges, given the frequency of open-label, non-randomised, single-arm studies on which to base clinical assessment and often high price tag driven by the need for specialised centres for administration. Current national models for reimbursement of ATMP are varied, which may add further complexity to decisions on PLEG that meet the requirements for all MSs.
  • The ability to address a potentially high number of PICOs for Oncology products where treatment and support is heterogeneous across EU MSs and the likely focus on overall survival data will be critical considerations for developers. These issues have been previously highlighted by EFPIA. Reviews published under the voluntary EUnetHTA process also include such challenges. For example, the scoping results for the Venetoclax, Glasdegib, Enasidenib and Regorafenib assessments all included best supportive care as a comparator and overall survival was listed as the top efficacy outcome.

Overall Impact for Medicines Developers

The introduction of Joint Clinical Assessments (JCA) and Joint Scientific Consultations (JSC) under the Health Technology Assessment Regulation (HTAR) represents a significant advancement in harmonising health technology assessments across Europe. While these processes aim to streamline evaluations and improve market access timelines, they require a proactive and strategic approach from developers of medicinal products. Successfully navigating these requirements entails careful planning and a clear understanding of the expectations for clinical evidence.

For developers, engaging early in the JSC process ensures alignment with HTA standards and minimises the risk of producing misaligned evidence, while effective preparation for JCA enables smoother submissions and faster decision-making. These processes can be complex, but they also offer significant opportunities for developers who take the time to integrate them into their overall product strategy.

Optimise Your JCA and JSC Submission

As the Health Technology Assessment (HTA) landscape continues to evolve, developers who seek expert guidance and adjust their strategies to meet these new requirements will be well-positioned for success in the competitive European market. Our regulatory experts at DLRC, along with our HTA partners, are poised to optimise the JCA and JSC submission processes by providing strategic insights, managing technical details, and ensuring compliance with the latest guidelines. For further information, please reach out to us at hello@dlrcgroup.com.