The US Patient-Centered Outcomes Research Institute (PCORI) celebrated the start of 2016 by putting comparative effectiveness research (CER) under the spotlight with a series of webinars focused on understanding stakeholders’ views on the controversial subject, amongst widespread concerns over rising drug costs. As a public-private entity created by the US Affordable Care Act in 2010, PCORI’s goals include setting research priorities, helping funding of key studies and establishing methodological standards for CER.

One particularly interesting PCORI webinar presentation relates to meeting stakeholder needs for CER, drawing on purchaser, payer and industry perspectives. This was based on the research project undertaken by the US Rand Corporation on behalf of PCORI. The project results are broadly in tune with findings of a 2015 drug-focused survey involving US and key European payers, although relativeness effectiveness (RE) is the term preferred in Europe. Together, these materials give insights into the evolution of drug-centered payer requirements in terms of CER/RE, a topic we covered as part of syndicated research a few years ago.

The PCORI project, based on telephone interviews and focus groups, found that US payers and industry stakeholders are favorable to randomized study designs and large study samples. The US/European payer survey also concluded that traditional randomized clinical trials (RCTs) will remain the preferred source of CER evidence through 2020, whilst direct head-to-head comparisons continue to be extremely relevant to their decision-making. Researchers from PCORI, the US Center for Medical Technology Policy and the UK Office of Health Economics conducted this survey with funding support from key pharmaceutical firms.

Traditional RCTs remain an essential component for assessing CER due to minimal bias and confounding whilst also having high internal validity and low measurement error. But US/European payers recognise the need to use some non-RCT data, mainly driven by their interest in “real world” evidence. Other well-known limitations of RCTs include their design to establish efficacy and not effectiveness, tendency to exclude multi-morbid patients, and generally limited follow-up period.

From RCTs to PCTs

As such, US payer/industry representatives in the PCORI project view “real world” studies favorably, but had different thoughts on design elements and dissemination of interim results. Payers suggest that the design should consider the “usual care” for specific populations after input from insurers whilst being cautious about the publication of interim results as opposed to waiting until the availability of final results. Industry members believe it is useful to provide additional information about the study design and caution that publication of interim findings should depend on the individual study. There was support for dissemination of clinically meaningful interim results.

The US/European payer survey supports greater use of observational studies and “real world” RCTs (or pragmatic clinical trials, PCTs) because of preference for appropriate comparators and information on real-world patients. Retrospective observational studies- which examine existing insurance claims, medical records, and clinical registries- tend to be large, readily available, and relatively inexpensive to process. However, these nonrandomized studies may be confounded or biased in their findings, despite significant progress in analytical methods to minimize potential unknown influences on outcomes.

Therefore, though not as strictly controlled as in traditional RCTs, PCTs can provide strong evidence about the effectiveness of one intervention compared to another in real-world settings. Such studies are generally conducted with patients of diverse medical and demographic backgrounds, as seen in clinical practice. Although logistically challenging given the diversity of patients and clinical practices, this comprehensiveness permits a better understanding of the expected impact of an intervention under routine practice. There is an expectation that Phase III PCTs might become increasingly feasible, affordable and appropriate to help with payer decision-making while still maintaining high internal validity.

Cost-effectiveness still divides opinions

In the US, the inclusion of cost-effectiveness evaluations into government-sponsored CER programs remains a sensitive topic. There is a public concern that reflections on cost could result in healthcare rationing and in turn create barriers to patient access. Congress has limited the ability of PCORI-funded CER to consider costs, which in the view of US payers in the PCORI project is a barrier to its usefulness. Biopharmaceutical industry members, on the other hand, support the restrictions on cost-effectiveness analysis but generally believe in the tailoring of CER information, including costs, to the needs of payers. These members highlighted the inclusion of cost information as part of self-funded CER-type studies at the request from payers.

As healthcare costs continue to escalate, attention to the importance of CER is growing in the US, with critics accusing PCORI of largely ignoring the comparative evaluation of prescription medicines. On the other hand, the privately funded Institute for Clinical and Economic Review (ICER) continues to grab headlines with the publication of comparative clinical effectiveness and cost-effectiveness analyses of high-cost drugs.

Although there is no formal requirement to submit an economic evaluation in the US compared to certain European jurisdictions, the pharmaceutical industry is advised to provide comparative evidence for their products to gain market access. The emphasis on comparative data by itself through head-to-head trials in real-world practice implies greater development costs for the industry due to studies requiring more resources, involving larger patient groups and longer follow-up periods. The additional expenditure could have a knock-effect on future pharmaceutical R&D pipelines.

Many countries, including key emerging economies, have started to take steps to start using CER in coverage evaluations of health technologies. Key to the widespread adoption of CER will however be finding a sustainable approach for the pharmaceutical industry so as to ensure there is not a double-whammy of cost-containment and prohibitively expensive comparative evidence generation.