ne of the unexpected impacts of the social isolation and distancing policies mandated during the COVID-19 pandemic has been growing interest in the use of real-world evidence (RWE), as an alternative or a complement to evidence provided by traditional randomized clinical trials (RCTs), for regulatory review and approval of therapeutic products.

Past into Present

According to a review co-authored by the Duke-Margolis RWE Collaborative, FDA regulatory review and approval considered 34 uses of RWE from 1954 to 2020. Most of these use cases came from rare disease or orphan drug communities in oncology, hematology, and neurology: therapeutic areas where patient recruitment and ethical considerations can challenge traditional RCT models. Fifty percent of these approvals were for rare conditions, and more than 80% received orphan drug designation.

Another recent study utilized a detailed clinical registry from 68 hospitals to analyze the off-label use of tocilizumab to treat patients with life-threatening inflammation early in the pandemic (March to May 2020) and concluded that in-hospital mortality was lower in patients treated with tocilizumab in the first two days of admission compared with patients whose treatment did not include early use of tocilizumab.

A more globally focused study has explored how RWE was used in regulatory applications submitted to the three founding ICH regulatory authorities—EMA in the EU, FDA in the US, and PMDA in Japan—plus Health Canada, from 1998 to 2019. Findings from this study include:

• Application of RWD for regulatory decision making has increased
• RWD has mostly been applied to rare diseases in which RCTs may be unfeasible
• RWD has been applied across all age populations, from children to adults
• RWD has mostly been sourced from electronic health records (EHRs) and registries
• RWD has been used as both primary data (when non-comparative data is available) and as supportive data (when validating findings).

This study also included several recommendations to help advance the science and applications of RWD and RWE:

• Changes to healthcare and medical information collection and platforms could optimize the downstream potential of this information as RWE
• RWE offers significant potential in cases where alternative study designs may be difficult
• RWD has significant potential in supporting clinical studies to accelerate approval of new medical products for patients in critical need.

One significant challenge is that there are so many different types of data in real-world settings, from insurer and hospital databases to patient electronic health records (EHRs). These growing types of data, and types of data collection and transfer (through wearables, for example), keep complicating the identification and collection of these data for evidence.

Relevance and reliability are vitally important in these data frameworks:

Relevance: Well-defined clinical outcomes and endpoints; representative and accurately defined target populations; and identification of biases (including missing data) and how to mitigate them.
Reliability: Integrity of data collection sources and processes, including audit trails; consistency of data over time across different sources; and quality control embedded in data management processes.

Determining whether the data are “fit-for-purpose” is essential. The continued evolution in data management technology and artificial intelligence adds new data analysis methods, but these need to be better understood, too. If the data are unreliable or the analysis is inappropriate, the results may be uninterpretable.

Moving Forward

The Duke-Margolis RWE Collaborative has generated several guiding documents on real-world data quality and relevance, fitness for use, developing study endpoints in real-world settings, and related topics.

The Reagan-Udall Foundation’s COVID-19 Evidence Accelerator, upon FDA’s request and in collaboration with Friends of Cancer Research, has been conducting observational studies to help speed the development of COVID-19 therapeutics, diagnostics, and vaccines—examining questions that in pandemic circumstances are difficult to explore in an RCT.

To assist sponsors working to incorporate RWE for regulatory submissions in the US, FDA’s CDER is planning to issue four RWE guidance documents by the end of 2021:

• Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drugs and Biological Products
• Regulatory Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drugs and Biological Products
• Using Registries as a Real-World Data Source for FDA Submissions
• Meeting the Substantial Evidence Standard Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence.

FDA’s Project Patient Voice, in its Oncology Center of Excellence, provides another good example of an RWE study focused on patient outcomes that cannot be studied or would be extremely difficult to study in traditional RCTs.

Hopefully, continued focus on patients and patient outcomes will provide compelling impetus that keeps the regulatory application of RWE science moving forward.