When can RWE translate into credible evidence? EMA officials discuss
Real-world evidence (RWE) may provide an opportunity to learn more about a drug’s benefits and risks, but officials from the EMA said in an article published Tuesday in Clinical Pharmacology & Therapeutics that there will need to be adequate statistical methods to extract, analyze and interpret RWE before they can translate into credible evidence.
In order to ensure that any new analytical methods are acceptable for regulators, the EMA authors say they will require testing and validation in nearly the same way as a new medicine is evaluated: “prospectively, well-controlled and according to pre-agreed plan.”
They add: “The ultimate key to achieving credibility is to start with an open but ‘agnostic’ mind-set and submit novel methods to a fair, transparent and prospective validation exercise; this cannot be done only by dry runs with old products. It is understandable that drug developers are wary of jeopardising the development programs for their valued new assets. However, we emphasise that if developers want trial assessors to accept novel methods, they will have to expose some of their experimental drugs to methodology development exercises.”
The officials also note that an upfront agreement on a “firewall” is necessary to ensure that an evaluation of methods will neither jeopardize nor rescue a product.
“We are aware that interest in conducting head-to-head RCTs [randomized controlled trials] in the post-marketing phase is often limited, but what is needed is at least several RCTs comparing two (or more) treatments that have been on the market for a sufficient period of time to enable simultaneous RWD analysis. This would provide an opportunity to ‘bolt-on’ a methods evaluation exercise by simultaneously developing the RCT protocol and the parameters of the RWD analysis which is to be conducted concurrently with the RCT but before RCT results become available,” they explain.
In a section on replacing RCTs with RWD analysis, the authors note: Prospectively designed new RWD studies to match the design of planned RCTs “is feasible when both drugs have been in routine use for a sufficient time. The concurrent approach avoids bias by matching the RCTs and RWD analyses as closely as possible (e.g. for patient characteristics, dose regimens), while avoiding the temptation to trim RWD analysis to the RCT results once they become available. It also allows for sensitivity analyses to identify whether alternative designs or analyses could have improved agreement between the designs.”
And while noting that any efforts in the RWE space are long-term projects that “will not come to fruition as a result of short term efforts by individual players,” the EMA officials also stress that the stakes are high for “overcoming methodology aversion and ensuring that all stakeholders arrive at a nuanced view between categorical rejection and naïve adoption of novel methods.”
RAPS: First published in Regulatory Focus™ by the Regulatory Affairs Professionals Society, the largest global organization of and for those involved with the regulation of healthcare products. Click here for more information.