Joint clinical assessment in the EU: Pan-European HTA for drugs and medical devices will become reality
By Xcenda
Updated: January 21, 2022
With the new European Union (EU) Health Technology Assessment (HTA) regulation coming into force in January 2022, the transition phase to a European joint clinical assessment (JCA)—which will be applied in full for certain drugs from January 2025—was initiated. This article aims to provide an overview of the current understanding of the new process and time frame of implementation, as well as some considerations for manufacturers.
Following the introduction of the centralized procedure for drug approval in the EU in 1995, which provides the European Medicines Agency (EMA) with the mandate of evaluating efficacy and safety of pharmaceuticals, the EU is now about to implement profound activities to harmonize the clinical assessment of drugs and medical devices in its 27 member states. With regulation (EU) 2021/2282, adopted December 15, 2021, the EU aims to replace the redundant evaluation of clinical evidence performed by multiple national HTA bodies, such as G-BA in Germany or HAS in France, and more closely link and align these clinical assessments. In this context, the relative effectiveness of drugs compared to standard of care, with particular attention to patient relevance, is thus gaining political importance at the EU-policy level.
The overarching political motives for establishing these processes are to avoid multiple country-specific assessments and to improve the functioning and transparency of a single market for health technologies. Through this legislative initiative, the evidence required by a newly created appraisal process, theJCA, is to be submitted only once, at the European level.
However, it is important to understand that in accordance with the founding principles of the EU, the organization of health services, allocation of resources and reimbursement, as well as pricing decisions remain under the sovereignty of the member states.
While such harmonization might lead to a reduction of redundant HTA activities at the manufacturer level as well as benefit countries which are not equipped with in-depth HTA expertise and/or infrastructure, this is a new and evolving process that is likely to impact the way manufacturers approach the market access hurdles in Europe. Therefore, manufacturers should remain close to the updates to ensure informed strategic planning for their pipeline assets.
JCA: The central pillar of the new EU-HTA regulation
The JCA will be organized and coordinated by the “Member State Coordination Group on Health Technology Assessment” (Coordination Group) that will be composed of representatives of all EU member states. Similar to the scientific evaluation of marketing authorization applications by the EMA, the JCA will be conducted by an assessor and co-assessor. These assessors will be from different member states and will carry out the clinical assessment, prepare a draft report, and consult relevant stakeholders. The Coordination Group will thereafter approve the reports, which will then be published by the European Commission. The timing of JCA for medicinal products will be coordinated with the central marketing authorization procedure (ie, EU Commission granting marketing authorization), ensuring its timeliness for supporting member states’ decision making at the time of launch. It is of particular importance that the JCA at EU level is strictly separate from value judgments, especially in terms of medical added benefit, which will continue to be made exclusively at the national level.
Starting with oncology drugs and advanced therapy medicinal products in 2025, the JCA’s mandate will be to systematically assess all available clinical evidence for new drugs. Once fully implemented by 2030, all drugs that will be registered by the EMA via the centralized procedure will be subject to a JCA. The JCA is designed to take different member states’ specific requirements into account, namely the definition of the standard of care against which evidence needs to be provided and the priorities and preferences regarding clinical outcomes. The further provision of country-specific evidence and clinical data will therefore most likely be needed.
The value of early engagements
In order to be prepared for the JCA, early engagement with assessors will be possible (and is advisable) to gather information and interact with the assessors via Joint Scientific Consultations (JSC). This allows manufacturers to engage and obtain input from EMA and HTA bodies on the clinical development program, pivotal trial design, and additional evidence needed for the assessment of specific pipeline assets.
From 2021 to 2023, the development of guidance documents on methodology, JCA, JSC, and transversal activities to be adopted by the Coordination Group is supported by the European Network for Health Technology Assessment (EUnetHTA) 21. The draft guidance documents developed under EUnetHTA 21 will be subject to public consultations starting in May 2022. Under this framework, JSCs led by EUnetHTA 21 partners in parallel with EMA scientific advice started in January 2022. However, taking the available resources into account, only a very limited number of annual JSCs will initially take place. A first open call for JSCs closed in December 2021, with a second open call planned for Q3 2022 to offer in total 8 JSCs for medicinal products or at least 6 JSCs by September 2023. The JSC application form for the second call is expected to become available in September 2022 on EUnetHTA’s website. Requirements for the first open call may be used as initial guidance to prepare for the second open call. Candidates for JSC are selected in two steps comprising the assessment of the products in regard to essential criteria, such as unmet medical need and first-in-class products, and additional criteria, such as targets a life-threatening or chronically debilitating disease. An essential prerequisite for a JSC is that the clinical trial (phase 2 or 3) has not yet started.
What are the upcoming steps on the road to JCA?
In addition to drugs, Class IIIb/IV medical devices and in vitro diagnostic medical devices could become subject to a JCA. However, contrary to drugs, manufacturers of these types of medical technologies can be called by the Coordination Groups to submit comparative clinical data. The call to submit data will be based on defined criteria, eg, unmet clinical need, first-in-class technology, potential impact on patients, impact on public health and healthcare systems, and the involvement of artificial intelligence. As a result, ensuring preparedness will be key for manufacturers, to ensure the appropriate evidence will have been generated and will be available for evaluation upon JCA’s request.
Outlook and discussion
As already mentioned, the harmonization of clinical assessment at the European level might lead to a reduction of redundant HTA activities and benefit countries which do not have established HTA expertise or infrastructure. However, the JCA process could result in increased requirements for clinical evidence generation as relative effectiveness and relevance of outcomes to patients gain further importance for drugs to successfully access each market. Thoughtful and informed decision making in the selection of comparators and outcomes in clinical development programs will become even more important to maximize success in market access.
It remains to be seen whether the stepwise approach (JCA at EU level, consideration of specific evidence at member state level), could even delay market access of new medicines. This refers to the extent and nature of evidence mandated by the central JCA vs the amount of evidence that is asked for by the individual member states. In other words, a lean and potentially consensus-orientated, “one-size-fits-all” JCA process might require the generation of additional evidence at the member state level with negative effects on market access timeliness and efforts needed by companies to assemble all necessary evidence. One prominent example would be the consideration of country-specific comparator therapies for which pharmaceutical companies need to provide comparative evidence, eg, through indirect comparisons. In addition, in order to be of value in decision making at the country level, a joint assessment should also consider different methodological approaches and individual perspectives of the member states, eg, definition of subgroups and surrogate parameters, and differences in interpreting the patient relevance of endpoints.
Another implementation-related consideration relates to the retention of country-specific regulations and principles, eg, currently an appropriate comparator does not need to be defined for orphan drugs in Germany as the added medical benefit is assumed to be proven by EMA approval.
A number of countries have unique HTA perspectives and processes which are tailored for orphan drugs, so given the mandated JCA for these therapies, it will be key to understand the relationship between the appraisal of these treatments at the EU-HTA level vs the actual inclusion of those findings in potential local market access processes implemented afterwards.
In addition, it is thought that companies will have to submit their JCA dossiers 45 days before the Committee for Medicinal Products for Human Use (CHMP) makes its final decision on the marketing authorization (Article 10 [1] of [EU] 2021/2282). As the final labeling will only be announced at the time of CHMP opinion, this may lead to considerable uncertainty when compiling the JCA dossier.
Last but not least, important operational questions will need to be answered. The development of medicinal products and the timing of the marketing authorization are subject to many uncertainties. Therefore, it would be desirable that existing approval pathways in the member states remain valid for a transitional period (yet to be defined) once the binding JCA comes into force.
So, what does this mean for pharmaceutical companies? First of all, JCA will significantly change market access and the interaction of companies with HTA bodies. However, at this early stage, it is not possible to judge whether the intended efficiencies will materialize to the extent thought or whether the requirements may even be increased in some cases. It also remains to be seen to what extent the JCA will consider or retain country-specific regulations. As a result, pharmaceutical and medical device companies should keep a close eye on activity generated by the development and implementation of the new EU-HTA infrastructure initiated in January 2022.
The article should be referenced as follows:
Kulp W, Martel M, Billig S, Schmidt K, Martinez J. Joint clinical assessment in the EU: Pan-European HTA for drugs and medical devices will become reality. HTA Quarterly. Spring 2022. https://www.xcenda.com/insights/htaq-spring-2022-joint-clinical-assessment-eu/
Sources
- EUnetHTA. A future model of HTA cooperation. White Paper. Diemen (The Netherlands): EUnetHTA; 2021. Accessed January 13, 2022. https://www.eunethta.eu/future-model-of-cooperation-fmc-white-paper/
- EUnetHTA. Joint HTA Work. Accessed January 13, 2022. https://www.eunethta.eu/jointhtawork/
- EUnetHTA. Joint Scientific Consultations (JSC). Accessed January 21, 2022. https://www.eunethta.eu/jsc
- EUnetHTA 21. Stakeholder Kick Off Meeting 3 December 2021. Accessed January 13, 2022. https://www.eunethta.eu/wp-content/uploads/2021/12/EUnetHTA-21-Stakeholder-Meeting-03.12.-FOR-WEBSITE.pdf?x16454
- European Parliament and the Council of the European Union. Regulation (EU) 2021/2282 of the European Parliament and of the Council of 15 December 2021 on health technology assessment and amending Directive 2011/24/EU; 2021. Accessed January 13, 2022. https://eur-lex.europa.eu/eli/reg/2021/2282/oj