Real World Evidence: Should I stay or should I go?

Inspired by #COVID19 and my contribution to flattening the curve by stay-at-home orders causing a little stir craziness, The Clash song “Should I Stay or Should I Go?” popped into my head. This is an opportunity to inject a little levity during this serious pandemic while also continuing my post series on the value of real-world data (RWD) to generate real-world evidence (RWE) in regulatory decision-making (RDM). 

Darling, you’ve got to let me know, should I stay or should I go? The NEJM article published 13/Feb/2020 on“The Magic of Randomization versus the Myth of Real-World Evidence” first put these schizophrenic and dichotomous thoughts of should RWE stay or go in my head. Then as we entered into the sobering realization of this C19 contagion, the debate of using RWE vs randomized controlled trials (RCT) to evaluate the safety and efficacy of chloroquine made me think of this again. Now I’ve been homebound long enough that the topic & song is permanently stuck in my head, so I figured I’d post about it.

It’s always tease, tease, tease. Industry (Pharma, Biotech, MedDev) has been intrigued by using RWE in RDM ever since the 21st Century Cures Act (Cures Act) was enacted in 2016. The Food & Drug Administration (FDA) even published a strategic RWE Framework outlining a multifaceted RWE Program exploring potential regulatory uses of RWD. The RWE Framework recognizes the potential integration of RCTs into the healthcare system to leverage data from routine standard of care to generate RWE for regulatory submissions (e.g., trials with so-called pragmatic elements). The Framework also highlights the need to explore the use of tools to enable better accessibility, connectivity, organization, and analyses of RWD, such as those from electronic health records (EHRs), medical claims, pharmacy dispensing data, or data captured using digital tools. One of the key objectives of RWE is to understand observations and events in the broader patient population in routine clinical practice settings.

Well, come on and let me know, should I stay or should I go? Pragmatic, hybrid, and decentralized study designs that incorporate RWD can help clinical trials become more agile and efficient by reducing administrative burdens on industry/sponsors and those conducting trials, and can allow patients to receive treatments from providers without compromising the scientific integrity of the trial or the quality of the data being collected. Leveraging ways RWD is transformed into RWE using transparent data standards that can give all stakeholders (industry, regulatory agencies, payors, health systems, providers, patients) confidence in the data’s provenance. 

If I stay there will be trouble. If I go, it will be double. Nevertheless, industry has been slow to implement this because of the challenges in RWD, despite FDA’s efforts to implement the provisions of the Cures Act. Some of the troubles in RWD utilization for RDM purposes are related to fragmented data sources, inconsistent quality, manual abstraction of unstructured data, privacy requirement across regions, lack of standard endpoint definitions & validation, variable assessment intervals, and varying EHR platforms. But without capitalizing on the benefits of RWE, trials will continue not only be costly, but take longer to complete within a limited population under study that produces a suboptimal safety and effectiveness profile within the larger population for which it may be used without necessarily ensuring higher data quality.

Come on and let me know; should I cool it or should I blow? In continued efforts to help industry embrace the use of RWD, the FDA Center for Drug Evaluation & Research (CDER) released on 11/Mar/2020 a request for application (RFA-FD-20-030) to specifically explore the use of RWD to generate RWE in RDM, and related issues such as data analytics, the use of digital health tools, and innovative trial designs utilizing healthcare settings. This RFA makes it clear to me that RWE should “cool it” and “stay”. 

Should I stay or should I go? Perhaps instead of such a dichotomous viewpoint that seems to exist, RWE and RCTs can co-exists leveraging the best of both worlds? Paraphrasing from Scott Gottlieb’s concluding remarks from 28/Jan/2019 speech, we should ensure that all our patients benefit from the full potential RWE and RCT technologies to make our healthcare system safer, smarter, and move patient focused.

I hope everyone is taking precautions and staying healthy during this C19 pandemic. Let’s continue the conversation.

(Now if this song is not completely stuck in your head, here is the "official" You Tube video in order to get it stuck in your head. You’re welcome!)