In July 2024, CPE, together with The Alliance for Regenerative Medicine (ARM) and Fondazione Telethon, issued a joint call to action on the EU’s Joint Clinical Assessment (JCA) process, now endorsed by 39 organisations. Our primary concern is that the methodological guidelines for the JCA may restrict the use of non-randomised evidence, like single-arm trials, which are often the only evidence available for Advanced Therapy Medicinal Products (ATMPs), such as gene and CarT cell therapies.
We believe that such restrictions could limit patient access to these lifesaving therapies. In addition to that, Randomised-controlled trials (RCT) may not only be unfeasible but also unethical. Several factors render RCTs infeasible or unethical for such ATMPs, including:
- Small enrollable rare disease populations often do not support multiple treatment arms.
- It is unethical to deny treatment through placebo in the case of severe progressive diseases and patients that ATMPs treat.
- Often a standard of care does not exist or does not halt the progression of disease.
- The limited treatment window for progressive degenerative diseases in children would be missed by assignment to placebo or standard of care.
- The complexity and burden of treatment makes blinding or add-on trial designs infeasible and/or unethical.
Why does this issue deserve attention?
- Limitation of Evidence: The methodological guidelines for the JCA process might undervalue non-randomised evidence, risking the dismissal of innovative and lifesaving treatments.
- Methodological Overreach: The JCA methodological guidelines may allow assessors to exceed their mandate by judging evidence sufficiency, contradicting the HTA Regulation.
Reactions and positive outcomes
In response to our concerns, the European Commission provided clarifications in a letter dated 21st August 2024. In their letter, the Commission indicated that the studies submitted for the JCA will not be limited to randomised controlled trials (RCTs). It acknowledged the unique circumstances surrounding the clinical development of ATMPs which would warrant the use of non-randomised evidence, including single-arm trials and real-world evidence (RWE). The European Commission has also clarified that the decision on the acceptability of the evidence and the validity of direct or indirect comparisons would remain within the competence of each Member State based on the JCA report. JCA assessors will not make definitive judgments about the acceptability of evidence. This feedback from the European Commission was also reflected by the HTA Coordination Group during the HTA Stakeholder Network meeting in June.
Read the Commission’s letter
Ongoing Concerns and Next Steps
CPE welcomes the European Commission’s clarifications. However, we remain cautious that a rigid interpretation of the methodological guidelines concerning the acceptability of non-randomised evidence as compared with evidence from randomised-controlled trials by some assessors could lead to a negative impact on the evaluation of innovative treatments, particularly ATMPs.
As such, we call for these methodological guidelines to reflect the position of the European Commission and the EU HTA Multistakeholder Network. Given that such revisions could take months, if not years, we ask for this position to be considered by the HTA Coordination Group in its assessments in the meantime.
We remain committed to ensuring timely and equitable access to transformative therapies for all patients across Europe.