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Volume 39, Issue 6
Its use, new data shows, could boost the economic benefit profile of more “common” drugs-and better inform HTA and payer decision-making.
An analysis of 10 years of decision-making by health technology assessment (HTA) agencies shows that the use of external comparators could provide a clearer picture of the economic benefit profile of more “common” drugs-and better inform HTA and payer determinations
The practice of using external comparators for regulatory approval and health technology assessment (HTA) agency decision-making has long been the norm in the rare disease drug space. However, there is increasing evidence that comparators are also becoming more important in regulatory and payer decision-making in other circumstances.
External comparators, also sometimes referred to as “synthetic control data,” are used to provide context to a single-arm study where it would be impractical or unethical to design the study with a placebo or active comparator arm. External comparator data is any data generated from patients external to the parameters of the parent trial that can be compared to the outcomes of a clinical trial. The comparison could be conducted as an unanchored, indirect comparison requiring patient-level data or a real-world benchmark where no adjustments or simulation is made at the patient level. The type of data used will depend on what data is available, as well as the intended audience:
Some of the change in how external comparators are applied is being driven by the increasing use of genomics and personalized medicine in drug approval pathways. In many of these circumstances, we are essentially creating new “rare” diseases out of more common conditions by creating biomarker or genomic subsets. We are seeing this most frequently in the oncology space, although the expectation is that this will become the norm in other therapeutic areas as well. This sub-setting of patients creates the same pressures faced by rare disease research, where the only practical study design for ethical and practical reasons may be a single-arm study.
The conditions are right for external comparator adoption for other reasons as well. In addition to richer and more longitudinal RWD becoming increasingly available, we know regulators and payers are looking for application of RWD to answer research questions.
There have been increasing signals from regulatory bodies that this data is helpful in their decision-making, although no formal policy statements have been released. Similarly, HTA bodies have not established formal policies or direction on their use of external comparators in their decision-making. However, recent analysis of historic HTA decision-making shows a correlation between the increasing use of external comparator data and positive decisions.
A 2019 review of HTA decision-making in the past 10 years using IQVIA’s HTA Accelerator provided insights into payer decision-making-and supports the idea that external comparators are useful to HTA bodies when making reimbursement determinations for a particular medicine. Data scientists extracted and aggregated information and datasets from HTA reports of more than 100 agencies in 32 countries across all therapeutic areas.
A recent review of the available data, led by Dr. Dony Patel of IQVIA, identified 165 single-arm clinical trial submissions to HTA bodies between 1996 and 2018. The first instance of external comparators submitted with these single-arm studies was identified in 2011, and a year-on-year increase was observed, largely focused in oncology.
The analysis identified 44% (72/165) of single-arm submissions made with some form of an external comparator to give context to clinical and/or economic benefit of the product under consideration. Of those who submitted with this comparators data, we observed a 67% (48/72) positive recommendation, as compared to 55% (37/67) in studies where the data was presented without this contextual information.
This indicates the importance of showing clinical/economic context and benefit to aid in decision-making. However, it is important to recognize that the nature of HTA decision-making is based on many different inputs and factors, and a review of HTA decisions demonstrates that the quality of the external data provided, along with the applicability of the analytical method, were important considerations.
There is currently no formal guidance for the use of external comparators to contextualize data for single-arm trials in regulatory and HTA submissions. And the process of selecting the right comparator is challenging because it can be confounded by changing standards of care regionally and over time. For example, a data source may be available but may ultimately be determined to be of insufficient relevance for the product and therapeutic area at hand.
Review of past HTA decisions regarding the indication can be helpful when selecting external comparators; however, the most critical input will come from the HTA stakeholders themselves, preferably as part of an early engagement process. If it is determined that an external comparator will be helpful to decision-makers, the next steps are selecting the right comparator for the target market and determining how to source the data. Here, final decisions must consider the correct methodology for comparing this data to that of the clinical trial.
Understanding HTA familiarity and comfort level with these approaches will help with these decisions, and the industry’s knowledge will grow as more submissions resulting from these decisions reach the conclusion of the regulatory process. Continued analysis and understanding are needed while waiting for formal guidance.
In the absence of current guidance on external comparators, there is acknowledgement that new trial designs will produce new types of evidence, which will eventually become part of the HTA value dossiers. In a series of interviews of UK-based HTA experts documented in “The Future of Precision Medicine,” an article by James LoveâKoh et al. published in the December 2018 issue of PharmacoEconomics, it was noted that the increased sub-setting of patients and the subsequent increasing complexity in treatment pathways will likely raise the need for additional sources of evidence for HTA consideration.
While the environment for the development of that data is maturing, there is a lack of impetus on the part of most bodies for establishing the appropriate use of this data. There is some hope that newer legislation and regulations, as well as increasing standardization and usage of RWD in the coming years, will help fill the data usage gaps.
In these interviews, there was also open acknowledgment that observational data (registry, cohort studies, electronic health records) will increase in usage and utility in the next 10 years and be used more consistently in HTA decision-making.
The use of this data requires that the correct statistical and technical acumen be applied to control for the unique challenges of data and information collected for other purposes, including controlling for selection bias and confounding.
We fully expect that HTA bodies will release direction on external comparators in the future. Until that time, biopharmaceutical manufacturers can use the increasing examples of positive decisions associated with external comparators as their guide. Selection of the appropriate data source and methods for analysis will be critical to maximizing the value of external comparator data to support access and pricing discussions with HTA bodies. Continued review and observation of HTA decision-making will add to our understanding of this quickly evolving space.
Barbara Arone is Vice President, Business Operations Center for Advanced Evidence Generation at IQVIA