Trial design in oncology depends on multiple clinical and commercial factors, and the evidentiary demands of regulators may be prioritized over those of health technology assessment (HTA) agencies. Optimization of HTA submissions hence requires understanding methodological approaches to robustly demonstrate comparative clinical benefit, beyond usual trial analysis. Here we highlight three recent studies by Avalere Health which explore such options and their consideration at HTA.

How Do Different HTA Agencies Consider Adjustments for Treatment Crossover?  

Treatment crossover occurs when patients in the control group of a clinical trial transition to the experimental treatment during follow-up. This is often necessary due to ethical considerations or to support patient recruitment, but it introduces complexity and uncertainty in understanding a therapy’s true impact on overall survival. Methodologies have been developed that aim to estimate trial outcomes without treatment crossover. 

In the case of the National Institute for Health and Care Excellence (NICE) in the United Kingdom, where overall survival benefit may be critical in determining cost-effectiveness, there is a preference for case-by-case evaluation of appropriateness given specific assumptions and limitations of each statistical method (as described in technical support (TSD 24) and highlighted in previous research by Avalere Health).  

Our recent research investigated whether such adjusted results were considered in assessments by two key European HTA agencies: Germany’s Gemeinsamer Bundesausschuss (Federal Joint Committee; G-BA) and the Haute Autorité de Santé (French National Authority for Health; HAS). Both make decisions by assessing if there is evidence of significant clinical benefit. Comparing with 18 NICE appraisals which discussed adjustments for crossover, adjustment methods were only mentioned in two of the corresponding HAS and six of the G-BA assessments, hence appearing to have a limited impact.  

Adjusted OS results were statistically significant in only one of these cases, for a trial in melanoma. However, even in this example, the published HAS report did not include commentary suggesting relevance, while the G-BA expressed skepticism regarding the use of a non-prespecified adjustment method. We conclude that there are relevant differences between European markets in the ability to rely on technical adjustment to support survival benefit, and especially in the current absence of specific Joint Clinical Assessment guidance on this topic, market specific strategies to evidence survival benefit will be needed.  

How is synthetic comparative data used to support single-arm trials at HTA? 

Oncology drug approvals supported by single-arm trials (SATs) may be justified by trial feasibility and the benefits of speedy patient access. However HTA agencies often raise concerns for quality of evidence, with negative impact often seen on outcomes and pricing negotiations. Synthetic control arms are a type of external control, defined as cohorts of patients from external data sets (which may be from other clinical trials or real-world data) adjusted using statistical methods. Avalere Health research explored the methods used to supplement SAT data in HTA submissions in NICE appraisals and the impact on outcomes. 

Among the 30 technology assessments identified with SATs as the primary source of efficacy/safety data, only seven explicitly involved a synthetic control arm or relied on propensity score analysis. Among those seven, only two relied on real-world evidence. Standard indirect treatment comparison methods, such as matching-adjusted indirect comparisons, still appear to be the dominant approach for generating comparative evidence in NICE submissions involving SATs, likely owing to a lack of availability of individual patient data for competitor trials. Bias and confounders from observational and SAT data carry over into synthetic control arms, and was seen to reduce HTA agency confidence in comparisons.  

This is an active area to watch as synthetic approaches become more sophisticated, for example with the concept of “digital twins”, to understand if the theoretical benefits of synthetic approaches will be recognized in HTA decision-making.  

Can Trial Evidence Transfer between Therapy Lines Support SATs at HTA? 

To consider a further approach to mitigate the negative impact of SATs at HTA, we looked at the feasibility of utilizing transferred trial evidence between therapy lines. In some instances, timing of read-outs from trials evaluating a drug in progressively earlier lines of therapy means that evidence from Phase III randomized controlled trials (RCTs) in earlier lines is available to support HTAs of indications only evaluated in a SAT. Our research identified these cases, and sought to understand if this had a positive influence on assessments by European and Canadian HTA agencies.  

Seven HTA decisions (six in multiple myeloma and one in non-Hodgkins lymphoma) were identified where Phase III RCT data were leveraged as supporting evidence in HTA (re-)evaluations by the  Agencia Española de Medicamentos y Productos Sanitarios (Spanish Agency for Medicines and Health Products; AEMPS), G-BA, HAS, and Scottish Medicines Consortium (SMC; Scotland).  

Among these cases, there were three instances (two with AEMPs, one with HAS) in which the Phase III trial data seemed to make a positive contribution to the HTA outcome. Insufficient overlap between the characteristics of the Phase III trial population and the target indication posed a concern to all HTA bodies: variation in leniency to consider this data was seen between agencies. The research highlights transferred trial evidence as a potential strategy to mitigate the well-known negative impact of single-arm trial design on reimbursement and price: however, this will require careful anticipatory planning in trial populations, subgroup analysis and timing of data availability.     

Conclusion 

HTA guidance on acceptability of evidence continues to evolve (most notably associated with Joint Clinical Assessment) alongside advances in analytics that offer further potential solutions to decrease decision uncertainty. Beyond familiarity with guidance, systematic case review and expert consultation are essential for identifying the best strategies to maximize value recognition at 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:

• The perils of treatment crossover in clinical trials 
• Supplementing single-arm trial data in NICE submissions – are synthetic approaches leading the charge?
• Use of data from Phase 3 randomized controlled trials in earlier lines of therapy in support of noncomparative evidence from pivotal Phase 2 studies