Navigating the Challenges of Joint Clinical Assessment for Advanced Therapy Medicinal Products: Harmonising or Hampering HTA?
Mandatory Joint Clinical Assessment (JCA) is set to begin in January 2025, with advanced therapy medicinal products (ATMPs) and novel oncology products being the first treatments subject to the new regulation. JCA aims to harmonise health technology assessment (HTA) processes across European Union (EU) member states, expediting access to and improving availability of innovative medicines.
As with any new process at this scale, the JCA process will inevitably suffer from a number of teething issues. ATMPs are some of the most challenging therapies to evaluate due to life-long effects and cure claims. They are often developed for rare, debilitating conditions with small patient numbers and other limitations to the evidence base, meaning that any issues in the JCA process are likely to be exacerbated in the evaluation of ATMPs. Despite specialised HTA methods and processes for rare disease treatments having been developed at a national level in some European countries, ATMPs for rare diseases have struggled to achieve reimbursement due to challenges around the demonstration of significant, patient-relevant benefit and a lack of direct comparative data.1 With no explicit adaptations to the assessment process for rare diseases, there are concerns across industry that JCA will not be fit for evaluating ATMPs for rare diseases, and will therefore not meet its goal of improving availability of innovative medicines. Here we outline what we see as some of the key challenges and suggested solutions for manufacturers soon to lead ATMPs through the JCA process.
Small biotech, big burden
A major challenge related to JCA lies in the burden that is anticipated to be placed on manufacturers of treatments under assessment. Companies will only have 100 days from receiving the final JCA population, intervention, comparator(s), outcomes (PICO) scope to develop and submit their JCA dossiers (Figure 1), with no visibility on draft PICOs beforehand, and no opportunity to engage early with assessors, unlike in many current European national HTA processes. This will place a lot of pressure on companies developing JCA dossiers or generating data to fill evidence gaps that may be identified upon receipt of the final PICOs.
This challenge is likely to be more acute for manufacturers of ATMPs for rare diseases. These are often smaller biotechs with limited resources; in addition to biotechs, we have also seen non-profit organisations, such as academic institutions or charities with even fewer resources, starting to take on the regulatory applications and commercialisation of ATMPs.2 However, JCA will occur in parallel to the European Medicines Agency (EMA) regulatory procedure, requiring intensive resources from these small organisations attempting to manage both processes, which often have differing needs, over similar timeframes. This may result in small organisations requiring delays to be made to one or both processes.
Additionally, due to lack of established best practice, rare diseases are often characterised by wide, regional variations in standard of care and access to treatment. The EUnetHTA21 example PICOs scoping exercises for two orphan drugs resulted in five and nine PICOs across only 10 member states.3 The numbers of PICOs are likely to be even higher when considering the PICOs submitted by all participating member states. Satisfying all PICOs within the submission dossier under such tight timelines may feel an impossible ask for small organisations.
Figure 1: EMA and JCA parallel timelines
Figure adapted from European Network for Health Technology Assessment (EUnetHTA).4
Abbreviations: CHMP: Committee for Medicinal Products for Human Use; EC: European Commission; EMA: European Medicines Agency; HTA: health technology assessment; HTA CG: Health Technology Assessment Coordination Group; JCA: Joint Clinical Assessment; PICO: population, intervention, comparator(s), outcomes.
One process doesn’t fit all
A published comparison of European and United States (US) national HTA reports for rare disease treatments concluded that separate or adapted approaches for rare disease treatments may facilitate more structured and consistent decision-making.5 Reflecting the importance of this finding, many national HTA agencies have worked to developed separate or adapted methods and process for the assessment of rare disease treatments. For example, over the past couple of years, the French Commission de la Transparence (CT) has noted that single-arm studies may now be accepted subject to their methodological quality, and the Danish Medicines Council, Medicinrådet, has acknowledged the importance of using real-world evidence (RWE) to assess the effectiveness of treatments.6, 7
This is a stark contrast to JCA, in which specialised methods or processes for rare disease treatments do not seem to be applied. For example, the EU HTA Coordination Group’s methodological guideline for quantitative evidence synthesis states that single-arm evidence is likely to be “insufficient for estimation of the relative treatment effectiveness”,8 despite indirect comparisons in rare diseases often relying on single-arm evidence when randomised controlled trials (RCTs) are infeasible. Based on this guidance, it appears unlikely that RWE, which is also often a vital form of clinical evidence in rare disease HTA submissions, will be viewed in a positive light by JCA assessors. In the same vein, it is unclear whether JCA assessors may apply flexibility to their requirement for “a sufficiently large treatment-effect estimate”8 in the context of small patient numbers, or how a lack of long-term outcomes for ATMPs may be viewed by assessors.
Overall, whether or how flexibility will be applied to the JCA methods for ATMPs remains unclear. Assessors may fall back towards the most traditional and rigorous assessment requirements required across member states, such as in Germany, where the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) has expressed its scepticism around use of RWE in HTA.9 Overall, if the challenges of evidence generation in rare diseases are not considered during JCA, the resulting reports are likely to be inconclusive and less effective in reducing the need for individual member states to conduct their own assessments of the clinical evidence with the appropriate rare diseases context.
