Background 

Driven by the need to demonstrate the value of novel therapies to regulators, payers and healthcare decisionmakers without delaying patient access, several “new” clinical trial endpoints have emerged in recent years. The traditional prioritization of overall survival, as objective and highly patient-relevant, may continue, but there is a need for shorter-term endpoints, and endpoints that capture other patient-centric value to inform decision-making.  

Informed by the perspective and requirements of key health technology assessment (HTA) agencies on this issue, Avalere Health recently presented research at ISPOR Europe 2025 on HTA agency perspectives’ on the time-to-next treatment (TTNT) endpoint and the growing role of minimal residual disease (MRD) hematologic oncology trials. 

Emerging HTA Agency Perspectives on the Endpoint “Time to Next Treatment”  

Patients with certain indolent cancers may cycle through multiple lines of treatment.  There is value to both patients and the healthcare system at large when a given product delays the time until a subsequent treatment is required, which may be operationalized (in clinical trials and in real-world data analysis) as TTNT. TTNT can represent the clinical profile of a new treatment beyond its benefit in delaying disease progression, including tolerability and adherence to treatment. 

From a patient perspective, TTNT may be a more meaningful outcome than progression-free survival (PFS), as subsequent treatments may be increasingly burdensome. To understand the extent to which TTNT data can impact HTA outcomes, we conducted a targeted review of recent HTA reports of pharmaceutical products for four indolent hemato-oncology conditions. The review spanned March 2018 to March 2025 and included the influential HTA agencies Canada’s Drug Agency (CDA-AMC), the National Institute for Health and Care Excellence (NICE), Haute Autorité de Santé (French National Authority for Health; HAS), and Gemeinsamer Bundesausschuss (Federal Joint Committee; G-BA).  

The research found that TTNT data was submitted by manufacturers in the majority of assessments. Clinical experts consulted by both NICE and CDA-AMC noted that TTNT is an important and relevant outcome measure. Moreover, a NICE committee noted that TTNT may be a more meaningful outcome than PFS, the typical primary endpoint for indolent lymphomas.  

However, the impact of TTNT on HTA outcomes to date was limited. This was due to (1) general methodological criteria (i.e., designation as exploratory endpoint negating consideration by HAS and challenge of interpretation of single-arm trial data), (2) specific challenges for the endpoint (i.e., no apparent recognition as patient-relevant by the G-BA, lack of pre-defined clinically meaningful thresholds), and (3) HTA bodies’ focus on on traditional endpoints.  

Currently, there is an emphasis on survival endpoints, which is more challenging due to the time to reach data maturity in indolent cancers. Given the recognition of the clinical and patient relevance of TTNT by some influential agencies, manufacturers may wish to consider the benefits of including TTNT as a secondary endpoint in clinical trials and working to develop an understanding of clinically meaningful thresholds for TTNT in specific diseases.  

The Growing Role of Minimal Residual Disease in Hematologic Oncology Trials and Implications for HTA  

For many years, the Avalere Health team has followed and supported clients in understanding the access implications of MRD, both as a trial endpoint and a patient risk determinant and selection criterion for guiding initiation or cessation of therapy. In new research, we evaluate how often HTA agencies will be faced with MRD as a primary endpoint in the future, and consider how agencies may adapt their methodologies to accommodate the use of MRD while maintaining methodological rigour.  

MRD is an increasingly important endpoint for accelerating access to innovative therapies. It is particularly relevant to hematologic tumors, where it can be reliably measured and linked to clinical outcomes, as evidenced by the 75 initiating trials that featured it in 2024 (up from 10 in 2010).  

To date, relatively few trials used MRD as a primary endpoint; this was most common in trials in multiple myeloma, accounting for 3%-25% of trials per year in the past 19 years, followed by acute myeloid leukemia and chronic lymphocytic leukemia.  

HTA appraisals relying on MRD remain rare and inconsistent, with only three examples identified. Despite acknowledging the existing evidence showing an association between MRD negativity and recurrence/mortality, HAS and G-BA regard MRD as a non-validated surrogate endpoint. NICE, in contrast, consider MRD a predictor of relapse and included it among matched variables in indirect comparisons and economic analyses. 

It remains to be seen how HTA agencies will react to MRD as a primary endpoint and what level of maturity of progression-free survival or other evidence is required to support positive recommendations. Ongoing and future HTA deliberations will be critical to understand if patient access can be accelerated through demonstration of efficacy benefit through this measure. 

Conclusion 

HTA agency interpretation of clinical endpoints remains a priority topic for market access teams in oncology, requiring strategic thinking to consider methodological guidance and deliver robust and acceptable evidence of clinical, patient and economic value without waiting for long-term outcomes such as overall survival (which may be confounded by subsequent treatments or cross-over).  

Looking forward, we note continued regulatory evolution (e.g., use of patient experience data or selected biomarker-based endpoints), and anticipate a continuing gap between what is acceptable to regulators and payers/HTA. Avalere Health’s experts in global market access would be pleased to explore this topic further and understand how we could support you across key markets.  

To learn more, connect with us. 

Read our ISPOR Europe posters:

• How impactful is time-to-next treatment on health technology assessment outcomes in indolent cancers?
• Rising tide: the growing role of minimal residual disease in hematologic oncology trials and implications for health technology assessment