In a data-driven world, where everything can be digitalized, drug regulators and sponsors are increasingly looking beyond the confines of clinical trials. The use of real-world data (RWD) is becoming common in the clinical development process of a drug. RWD enhances the drug approval process, helps sponsors understand how a particular intervention really performs, and assists in clinical trial planning.

RWD is the data that is generated around patients’ healthcare status or through delivery of healthcare to the patients, in a real-life setting. (1) Real world evidence (RWE) is the evidence that is generated by the analysis of RWD.

Since RWD dramatically reduces the drug approval time, regulatory agencies have emphasized its incorporation into Randomized Controlled Trials (RCTs). This advancement was made possible in the USA by the USFDA’s 21st Century Cures Act, (2) which incorporates the perspectives of patients in the development of a drug, biologics or a device. This act enhances the ability to modernize the clinical trial design and assessing the clinical outcomes in the real world, accelerating the overall drug development process

Though the data from RCTs are considered as the gold standard for drug approval process, drug agencies view RWD as a new avenue to inform the regulators of drug development and expedite the approval process. RWD provides insights into the clinical outcomes of diverse groups of patients in response to various treatments and interventions in real world. This is in stark contrast to the highly regulated or manicured atmosphere in which clinical trials are conducted – where a new intervention is tested on homogeneous group of patients. Since the clinical trial environment cannot be replicated in a routine care setting, the treatment outcomes may vary from what was observed during a clinical trial and how the intervention performs in real world scenario.

With the advent of technology and digitalization in the past decade, it has become easier to collect and store the data into a digital database. The increasing use of smartphones, computers, biosensors and wearable devices into RCTs provides real-time, rigorous and robust data. RWD can be collected prospectively as well as retrospectively from pragmatic trials or from observational studies. Additional sources of gathering real-world data are electronic health records (EHRs), insurance billing and claims, patient registries, patient reported outcomes (PROs), and biometric monitoring devices.

FDA’s Historical Uses of RWE

Using RWD and RWE in regulatory decision-making for drugs and devices has been on the agenda of regulatory agencies for a few years now. There has been a surge in approvals of more drugs with the help of RWE by the USFDA. From 1995 to 1997, FDA’s approvals based on RWE were 19.4 percent, which jumped to 47.2 percent between 2015 and 2017. (3)

A few notable examples where the USFDA has used RWE for regulatory purposes are as follows:

  • The first instance of USFDA using RWE for regulatory approval happened in June 2017, when the USFDA approved a new indication for a medical device. The device, which is called a ‘Transcatheter Aortic Valve Replacement (TAVR)’ device, was first approved in 2011 on the basis of RCTs. Subsequent to its approval, the manufacturer established a product registry, which had around 1,00,000 TAVR records. Among these, there were around 600 instances of off-label use of TAVR for a ‘valve-in-valve’ procedure; based on this registry data, the USFDA approved TAVR for the new procedure, without requiring any RCTs, saving both time and money. (4)
  • On May 24, 2019 the USFDA approved Zolgensma (Onasemnogene abeparvovec) for a specific type of Spinal Muscular Atrophy (SMA) in children less than two years of age. (3)
  • On August 14, 2019, the USFDA approved pretomanid tablets as part of a combination regimen with bedaquiline and linezolid for treating a specific type of highly treatment-resistant pulmonary tuberculosis. (3)

Incorporating RWD into Clinical Trials: Smarter Clinical Trials

RWD and clinical trials is not an “either-or” situation. In fact, researchers can combine RWD and RCTs while investigating a medicinal product. RWD can support many activities during the clinical trial phases of drug development. For example, RWD can be used during the initial study design and planning phases to validate the study protocol feasibility. The use of RWD speeds up patients’ recruitment and numbers, compresses startup time lines and reduces the cost of evidence generation.

Researchers have developed “mosaic methodologies” to blend the components of traditional RCTs into newly found RWE. These methodologies are as follows: (5)

  • Extension: This approach begins with an RCT and patients consent to link their data from sources like EHRs. Thus, initially an RCT is conducted and follow-up data is linked later.
  • Augmentation: Here the RWE is used as a control data for a single arm study.
  • Enrichment: It combines primary data from patients and physicians with secondary data from EHRs and other sources. e.g., registries
  • Pragmatic randomization: In this approach patients are randomized first, initial data are collected and, follow-up is conducted using RWD. This is the best approach as it uses randomization and provides RWD for generalizability.

Nonetheless, there are certain barriers to integrate RCTs with RWE. The major barrier is the ‘traditional mindset’ that the results from RCTs are the best possible evidence. These are evidence hierarchies that put RCTs at the top and RWE at a lower level. In order to make change, these hierarchies need to be revisited. There is a lot of work needed on the technical as well as methodological sides to convince the decision makers that the RWD is addressing an important clinical question in a robust and valid manner.

Thus, the smart integration of RWD has the potential to improve the quality, impact, validity, generalizability, and trustworthiness of RCTs. Probably in near future, using RWD in clinical trials will be second nature, but we – as an industry – must work incessantly to get to that point.


  1. Real-World Evidence. Available from: Accessed 18 July 2020
  2. 21st Century Cures Act. Available from: Accessed 18 July 2020
  3. Christina Purpura. The surge in FDA approvals supported by RWE: A look at the three recent FDA developments. Available from: Accessed 29 July 2020
  4. Neil A. Belson. FDA’s Historical use of Real-World Evidence. Available from: Accessed 4 August 2020
  5. Barriers and Disincentives to the Use of Real-World Evidence and Real-World Data. Available from: Accessed 13 Aug 2020

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