External Control Arms (ECAs) provide comparative evidence when recruiting patients is difficult or unethical in randomized controlled trials. ECAs have significant potential to save resources and accelerate access to innovative treatment. In a previous blog, our experts took a deep dive into the concept of ECAs, their acceptable use cases, and the current regulatory guidance.

Existing guidance on the design and conduct of externally controlled trials emphasizes the importance of early engagement with regulatory and HTA bodies to justify using an ECA and discuss the preliminary study design and statistical analyses. With the increasing use of ECAs in regulatory and HTA submissions, the acceptable use cases for ECAs and important design and analytical considerations are becoming clearer. However, sponsors still face key questions about the optimal timing to plan for an ECA and how to prepare for early interactions to address differing regulatory and HTA perspectives.

In the ISPOR US 2024 HEOR Theatre session, Jason Simeone, Evie Merinopoulou, and Grace Hsu delved into these questions, discussing how regulatory and HTA stakeholders appraise ECAs, common issues from both perspectives and proposed practical solutions. In this blog, we ask Evie follow-up questions, highlighting insights from their ISPOR HEOR Theater session.

Your ISPOR US 2024 presentation was about early planning strategies for ECA. So, what is the optimal timing to start planning for an ECA?

Ideally, sponsors that need to perform an ECA to support their development program should start planning for the ECA alongside the clinical trial design. This allows them to gain experience with current real-world data (RWD) and make any necessary investment decisions for data improvements, such as additional data collection or infrastructure upgrades. Further, considering an ECA during the trial design provides the opportunity to incorporate real-world endpoints into the clinical trial. This is particularly valuable because defining clinical endpoints in real-world databases can often be challenging, especially when they are not measured consistently between routine practice and clinical trials.

Further, we showed in our presentation how although formal guidance from regulatory and HTA bodies on ECAs is consistent, final decisions when appraising ECAs may differ. This divergence in regulatory vs HTA acceptance reflects differing requirements for ECAs. When planning ECAs, both perspectives and requirements should be considered. Therefore, within sponsor organizations, early planning is key for cross-functional alignment (between HEOR/Market Access and Medical Affairs teams) on ECA study objectives and design, leading to more efficient evidence planning. With regards to external engagements with regulators and payers, the optimal timing is very contextual, but generally, sponsors should engage with decision makers via available routes like early advice programs, early enough to have the time to incorporate feedback and adjust their RWD strategy and study design—before protocol and SAP finalization.

Is early planning necessary for all cases? For instance, if a product is being developed for an indication with a rapidly changing treatment landscape and the appropriate comparators may not yet be known, would these early planning activities still be useful?

Yes, absolutely. During the early feasibility assessments that we discussed in our ISPOR presentation, we should evaluate a range of elements to determine the feasibility of an ECA—ranging from the identification of target populations to the reliable capture of confounders and study endpoints, among other factors. Identifying relevant comparators is only one element of those assessments. Even if comparators change over time, becoming familiar with RWD and current gaps helps inform discussions about the appropriate data strategy and design, which should be flexible enough to reflect some of the changes in the treatment landscape. Perhaps now, we would want to know if treatments are well captured and elements like patient count on a relevant comparator will need to be refreshed.  It is important to ask questions during the early planning stages that are specific yet broad enough to inform ECA feasibility, even if the research question evolves, particularly concerning the RWD strategy.

You’ve recommended that study sponsors should be prepared to discuss certain topics during early engagement meetings, such as the ECA rationale, data source, early design considerations, and feasibility assessment. In a resource-constrained environment, sponsors may not want to invest so much money in these activities before the very first meeting, only to receive a negative response. What topics should be prioritized for that first engagement with an HTA or regulatory agency vs. subsequent meetings?

This is an important point. Ultimately, the most crucial aspect is to clarify the justification for an ECA and assess whether the agencies are open to considering evidence from an ECA. Working with the right experts who understand agency requirements from prior experience is important. Beyond the justification for an ECA being clear, we see that most critiques of ECAs stem from data issues. So, in my opinion, presenting external data source options and discussing anticipated challenges can facilitate a more productive discussion in those early engagements. If resources are constrained, a more targeted review is sufficient rather than a full-blown data landscaping exercise.

During your presentation, you emphasized the importance of identifying fit-for-purpose data. However, in some cases, a sponsor may have to submit to an HTA body in a region where such data is not readily available. For instance, if a detailed data landscaping assessment reveals that most fit-for-purpose data is in the US, but the submission is for a European HTA agency, how can sponsors address this challenge in their submission?

First and foremost, sponsors need to present to the local agency that they have thoroughly attempted to identify a data source accurately representing the local (target) population of interest. Local agencies are usually quite understanding if sponsors can demonstrate that they made the necessary effort and did not cherry-pick data sources, but instead selected a source with the highest quality data available for the research question, in a transparent and systematic manner. However, this means that there might be some potential external validity bias that could concern a local decision-maker. For example, a UK or German payer might be concerned that evidence submitted from a US data-derived ECA may not be generalizable to the target population of the decision problem.

At Cytel, we have been engaged in some very interesting work to understand how we could adjust for this potential external validity bias using transportability methods. These are quantitative methods, similar to those adjusting for confounding, and can be reliably used to extend conclusions from one study population to an external target population. Essentially, if core evidence comes from a US-data derived ECA, transportability methods can be applied to adjust the study findings to measurable patient characteristics in the target population of interest, accounting for prognostic factors or effect modifiers. We recently published a demonstration project on this topic [1].  Additionally, NICE recently updated its RWE framework [2] to include transportability analysis methods.

Alternatively, sponsors could consider designing a prospective study, though this approach requires much higher costs and extensive timelines. If you’re taking this route, you should design data collection with the ECA in mind, aligning patient selection criteria, endpoint definitions, etc., which is why planning early is important.

Overall, at Cytel we encourage sponsors to approach data selection in a transparent and systematic way, as recommended across all existing ECA formal guidance documents, and leverage available analytical approaches to address potential external validity concerns when using non-local data if additional data collection is not feasible.

Which internal stakeholders should be involved in this process of early planning for ECAs, and what should sponsors consider when partnering externally?

Typically, in sponsor organizations, there are clinical development and medical affairs teams that understand regulatory requirements and processes very well. In addition, there are Market Access and HEOR/RWE teams that know RWD and real-world evidence methods very well. These teams may not always work closely together, but in our presentation, we talked about the importance of bringing these two teams together early on in planning for ECAs to align differing regulatory vs payer requirements. When selecting external partners, it’s important to work with organizations that have important methodological and technical expertise. They should also have a thorough understanding of the evolving guidance and acceptance criteria of decision-making agencies and be able to provide strategic guidance on important study design decisions and early stakeholder engagements.

Interested in exploring further? Download the slides from the ISPOR HEOR Theatre Session presented by Cytel here.

Notes

[1] Ramagopalan SV, Popat S, Gupta A, et al. Transportability of Overall Survival Estimates From US to Canadian Patients With Advanced Non–Small Cell Lung Cancer With Implications for Regulatory and Health Technology Assessment. JAMA Netw Open. 2022;5(11):e2239874. doi:10.1001/jamanetworkopen.2022.39874

[2] https://www.nice.org.uk/corporate/ecd9/resources/nice-realworld-evidence-framework-pdf-1124020816837

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