Pragmatic clinical trials. Single-arm studies. Synthetic trials. N-of-1. These are just a few of the innovative study approaches that are poised to transform biopharmaceutical research, especially in rare disease. Drug developers and regulatory bodies in Europe and the US are expanding the use of these research models, which rely on real world evidence (RWE) from sources such as natural histories, registries, patient records, and prescription and claims databases.
Yet, while research frontiers are expanding, market access in rare disease remains patchy, with patients in both the US and Europe encountering delays and other obstacles. American payers still insist on prior authorizations for virtually all rare disease treatments. And, in Europe, reimbursement deliberations may stretch for years after a breakthrough product clears regulatory review across the Atlantic.
A new survey by Syneos Health suggests that payers do not fully understand or value RWE when making reimbursement and formulary decisions. This might help explain some of the access barriers faced by patients and families with rare diseases.
How can manufacturers help narrow the understanding gap? And, is there a way for the biopharmaceutical industry to address payer concerns about RWE so that market access can keep pace with research innovation and regulatory change?
In our survey, we learned that many payers are not receptive to RWE-based representations or health economic forecasts in sponsors' dossiers or related conversations when it comes to rare disease. This is partly because they are focused on conditions, such as cancer, diabetes and cardiovascular disease, which make up a larger part of pharmacy and medical budgets.
And, while payers have been using RWE from their own claims databases for many years, they are not paying close attention to how regulatory use of RWE is evolving. As a result, internal processes followed by payers' Pharmacy & Therapeutics committees are not changing on a similar trajectory.
Most US payers associate terms like "RWD" and "RWE" with post-marketing surveillance or health economics outcomes research (HEOR), or, in some cases, submissions for label extensions. They don't assume that RWE can answer questions about the safety and efficacy of new drugs coming to market. European payers showed greater familiarity with RWE terminology but also voiced many questions and concerns.
By taking some of the steps described below, drug developers may be able to narrow the understanding gap with regard to RWE and improve market access for patients and families struggling with rare diseases.
- Bring clarity to RWE lexicons
In the Syneos Health survey, payer responses revealed vague associations with RWE and little sense of urgency around their use. Drug developers should catalyze industry-wide efforts to standardize lexicons around RWE and familiarize payers with their utility and merits. In addition, FDA guidance on the use of healthcare economic information (HCEI) today permits more far-reaching conversations between manufacturers and payers on topics including RWE. To avail themselves of new opportunities, manufacturers must boost internal literacy on HCEI guidance.
- Improve transparency around observational trials
As laid out by a joint industry task force on RWE, investigators embarking on prospective and retrospective observational trials should post the study protocol on a public site prior to conducting the analysis and show how ensuing results conform to the original protocol. Investigators should also create opportunities for other researchers to reproduce the study and publicly address any criticisms that arise. i
- Define registries used in single-arm trials
When designing a single-arm open label study of a rare disease treatment in the US, use of a historical control arm is key. Eligibility criteria for the historical arm should be well defined, including product registries vs. disease or condition registries vs. health services registries. Registries not only help accumulate data, they show the sponsor's long-term commitment to the community.
- Understand the virtues of expanded access programs
In addition to supporting the patient community, expanded access or compassionate use programs generate longitudinal data that may be of interest to payers. Recent FDA guidance on RWE specifically cites examples where the supportive RWE has consisted of data on historical response rates drawn from chart reviews, expanded access and other practice settings. ii
Most trial sponsors in the US. and Europe already seek scientific advice and support from regulators. Early in the development process, they should bring this same collaborative spirit to engagements with payers. For more information, download our report here.
ii https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence. See link on this page to "Framework for FDA’s Real World Evidence Program."
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