New EU HTA Guidance OKs Single-Arm Studies, But More Work Needed On Evidence Gaps
Executive Summary
New guidance from the European Commission on clinical trial validity for forthcoming joint clinical assessments has eased some concerns about the generation of evidence for rare disease treatments and advanced therapies.
New guidance on the validity of clinical studies for forthcoming EU-level joint clinical assessments is a step in the “right direction” as it acknowledges the role of non-randomized trials and single-arm studies in demonstrating the clinical effectiveness of new treatments, according to Alexander Natz, secretary general of EUCOPE, which represents small and medium-sized pharma companies in the EU.
However, more needs to be done to develop a framework for dealing with situations where gaps in the evidence remain and randomized controlled trials (RCTs) are not feasible, says the Alliance For Regenerative Medicine, which represents biotechnology companies, academic and medical research institutions, and patient organizations.
The European Commission published the new guidance on 23 September. It aims to “define, classify and assess the certainty of clinical trial results” that will inform JCAs in an “objective, reproducible and transparent way.” (Also see "HTA Regulation: EU Publishes Guidance On Validity Of Clinical Studies For Joint Clinical Assessments" - Pink Sheet, 25 Sep, 2024.)
JCAs were introduced under the 2023 Health Technology Assessment (HTA) Regulation, which is intended to boost cooperation on HTA across the EU. These EU-level assessments will be similar to the relative effectiveness assessments conducted by EU member state HTA bodies and will go live from January 2025 for rare disease products and advanced therapies.
Gold Standard RCTs
The guidance sets out the specific strengths, weaknesses and recommendations relating to different study designs. It states that randomized clinical trials remain the “gold standard” for estimating the intervention’s effect.
However, while it concedes that non-RCTs are likely to lead to confounding bias, it says that several methods can be used to control confounding, such as design-based or model-based methods.
The guidance also notes that single-arm trials do not allow for relative-effectiveness assessments when they are submitted as the only data source. However, “data from a single-arm trial can (at least theoretically) be used coupled with an external source of data as a control to allow for a comparative statistical analysis,” it says.
Right Direction
This is good news for industry, particularly companies that market orphan medicinal products (OMPs) and advanced therapy medicinal products (ATMPS), which have expressed apprehension around the evidence requirements relating to the guidance on indirect and direct comparisons. (Also see "Non-Profit Groups Rally To Remedy EU Joint Clinical Assessment Evidence Issues" - Pink Sheet, 17 Jul, 2024.) (Also see "New HTA Evidence Guidelines In EU Could Spell Trouble For Advanced Therapy Companies" - Pink Sheet, 26 Mar, 2024.)
Especially concerning for them was a statement in the methodological guideline on the use of non-randomized studies that cast doubt over the use of certain studies and evidence from non-RCTs and single arm-trials.
Nevertheless, Natz believes that the new guidance “is going in the right direction by acknowledging that the certainty of clinical study results cannot be seen independently from the disease context.” He added that this was highly important for rare diseases and cell and gene therapies “where low patient numbers and high unmet need limit the possible study methods.”
The new guidance also “acknowledges that non-randomized evidence can be valuable for JCAs and that single-arm trials will be accepted and reviewed by the assessors,” Natz observed. He added that this would be “critical to ensure that EU HTA will speed up access to innovative therapies for patients.”
“We look forward to further discussions in the HTA Stakeholder Network to ensure that the methodology for JCAs is tailored to the specificities of OMPs and ATMPs,” he added.
According to ARM, the guidance “opens up to the possibility - in cases when RCT are not feasible - of running indirect comparisons starting from single-arm trials that are ‘coupled with an external source of data’.”
Nevertheless, the absence of a framework on the best approach to evidence generation and indirect comparison when RCTs are not feasible and there are evidence gaps remains problematic, it said.
The alliance is therefore highlighting the “fundamental need to develop consensus” on what to do when RCTs are unfeasible, how to fill evidence gaps, particularly through real-world evidence, and the best approaches to running independent comparisons.