Real World Study (RWS): Revolutionizing Evidence Generation in Digital Healthcare

In recent years, with a deepening understanding of clinical research methodologies and the urgent demands of medical practice, Real-World Studies (RWS) have garnered increasing attention from medical researchers. On December 25, 2016, the U.S. Congress released the final version of the 21st Century Cures Act on its official website, proposing the use of “Real-World Evidence (RWE)” to support label expansions as an alternative to “traditional randomized controlled trials (RCTs),” a move that sent ripples through the industry.

Industry insiders believe that the introduction of this bill will accelerate the drug approval process, but it may also compromise the scientific rigor of reviews, potentially undoing the hard-won scientific evaluation system overnight and reverting it to its pre-reform state.

Real-world studies have once become the focus of industry discussions,What exactly is real-world study? How does it differ from traditional clinical trials? And what is its application status in the field of Traditional Chinese Medicine?In this article, VCBeat (WeChat: vcbeat) will lift the veil on real-world studies.

Real-World Study (RWS), originating from pragmatic clinical trials, falls within the domain of pharmacoepidemiology. It involves conducting long-term evaluations based on large sample sizes that cover a broader and more representative population of subjects. In RWS, treatment interventions are non-randomly selected according to patients’ actual clinical conditions and preferences, with an emphasis on meaningful therapeutic outcomes, thereby further assessing the external validity and safety of the interventions. Currently, RWS has garnered significant attention across many medical fields, with some disciplines having established relatively comprehensive observational cohorts, registries, and managed care databases.

Real-World Studies (RWS) are clinical studies conducted within real-world healthcare settings. From the patient’s perspective, they observe and evaluate the efficacy and adverse reactions of interventions across a broad spectrum of routine clinical practice, constituting patient-centered outcomes research. The core principle of RWS is to replicate real-world clinical practice conditions as closely as possible when studying interventions. Therefore, RWS possesses the following characteristics:

1. The study population is extensive with a large sample size; by employing broad inclusion criteria and minimal exclusion criteria, a cohort of subjects with no or minimal selection bias was obtained.

2. Treatment selection, including medications or other therapeutic measures, is based on the patient’s actual clinical condition and hospital protocols, rather than random assignment. In real-world studies (RWS) with a control group, the control arm receives treatments consisting of widely recognized effective drugs or interventions.

3. There is a preference for conducting long-term evaluations, with outcome measures primarily focusing on indicators of broad clinical significance, such as changes in disability status or quality of life, rather than targeting a specific symptom or characteristic.

4. There is no fundamental difference between RWS and RCTs or other types of studies in terms of data collection and statistical analysis. However, in RWS, researchers often need to collect more comprehensive information and flexibly apply existing statistical methods based on the type of data and the actual needs of the study.

5. By implementing strict control measures in data collection, management, and analysis, researchers aim to derive “real-world” conclusions through the conduct of real-world studies (RWS).

Modern medicine has evolved from the era of experience-based practice to the current era of evidence-based medicine, with the highest level of evidence in evidence-based medicine beingRandomized Controlled Trial (RCT). While randomized controlled trials (RCTs) are considered the gold standard for clinical trials due to their methodological rigor, they have limitations in practical application. In contrast, real-world studies (RWS) involve larger sample sizes and broader populations, reflecting final clinical outcomes following specific medical interventions and actual practices in real-world healthcare settings. As such, RWS findings offer stronger reference value for clinicians and provide more direct insights into patient experiences.

VCBeat (WeChat: vcbeat) has provided a detailed summary of the six main differences between the two:

nStudy Period and Study Objectives:RCTs focus on “Efficacy”Studies (efficacy trials); RWS focuses on“Effectiveness"Studies (effectiveness trials)."

nStudy Timeline and Design:RCTs typically have a shorter duration and are primarily experimental in nature; RWS employs longer-term clinical observation and follow-up, provides a robust assessment of health outcomes, and selects study designs based on specific research objectives and content.

nIntervention and Control Measures:RCTs require random allocation, blinding, and standardized treatment protocols, sometimes even involving the use of placebos. These requirements may limit the generalizability of the results, affect the likelihood of outcomes, and present drawbacks in terms of alignment with real-world clinical practice. In contrast, RWS is a non-randomized, open-label, unblinded study that does not use placebos. It more closely mirrors real-world healthcare settings, poses no challenges in generalizability, and yields relatively authentic and reliable results.

nResearchInclusion and Exclusion Criteria:RCTs typically enroll study participants under strict inclusion and exclusion criteria, with a broad age range. Their representativeness and external validity have certain limitations. In contrast, RWS adopts broader inclusion criteria and fewer exclusion criteria, obtaining a cohort of subjects consistent with the population to which trial results are extrapolated, thereby substantially reducing selection bias.

nIntervention Status:RWS emphasizes real-world treatment, while RCT emphasizes standardized treatment.

nOutcome Measures and Data Collection:Outcome measurements in randomized controlled trials (RCTs) typically focus on one or several specific symptoms or signs as evaluation targets, whereas outcome measurements in real-world studies (RWS) often adopt indicators with broad clinical significance, thereby offering greater clinical utility.

Although there are significant differences between RCTs and RWS, they are not in opposition but ratherComplementarity and Continuityrelationship. Randomized controlled trials (RCTs) are the foundation for evaluating any clinical intervention, used to assess efficacy and safety; without RCTs, the results of any external validity will be called into question. Treatment guidelines are developed based on RCTs, enabling new clinical interventions to be truly applied in clinical practice. However, guidelines are recommendations that inform physicians about what should or can be done, rather than what must be done, and they cannot replace clinical experience. Therefore, real-world studies (RWS) are needed as an effective supplement. RWS is used to determine effectiveness, allowing for the assessment of real-world benefits, risks, and therapeutic value in clinical practice, thereby bringing the conclusions of clinical research back to the real world after RCTs.

Real-world studies (RWS) are also referred to as “observational research,” “outcomes research,” “non-interventional research,” “epidemiological studies,” “post-marketing surveillance or Phase IV studies,” “disease or product registries,” and “pharmacovigilance studies.” Based on years of experience in the field of RWS, the VitalStrategic Research Institute has summarized the following categories of RWS.

Based on the primary research objectives and formats, RWS is broadly categorized into:Prospective Study、Retrospective StudyandMeta-analysis study,Prospective studies methodologically include registry studies, cohort studies, comparative effectiveness research, and patient-reported outcome studies.

From an application perspective, RWS can also include:

 ① Clinical Effectiveness Study:Observing medical indicators that represent clinical outcomes, such studies can evaluate the real-world effectiveness of multiple clinical interventions, monitor changes over various time periods, compare differences across regions, and assess actual clinical outcomes under specific conditions;

② Economic Benefit Study:This type of study evaluates the resources required to achieve a comparable level of clinical effectiveness, considering the budget impact of a healthcare intervention (such as a new drug, surgical technique, or diagnostic method) on the routine budget for managing a specific disease; such impact can be demonstrated through concepts like resource savings or resource utilization.

③ Epidemiological Studies:Observe the incidence of primary diseases, the incidence of complications, and factors influencing disease onset or progression under specific conditions;

④ Patient Feedback Survey Research:Under regulatory guidelines, patient-reported outcomes (PROs) that capture patients’ intuitive responses to specific treatments—including symptomatic efficacy, side effects, convenience, and quality-of-life indices—can be recognized by drug approval agencies such as the U.S. Food and Drug Administration (FDA) and incorporated as part of a new drug’s profile.

After Real-World Studies (RWS) were introduced to China, their methodologies were rapidly adopted by scholars of Traditional Chinese Medicine (TCM) and applied in TCM research. Currently, TCM primarily employs RWS to evaluate the efficacy and safety of drugs used in clinical practice or already on the market, as well as to design and assess research protocols for specific diseases.

Although randomized controlled trials (RCTs) are the “gold standard” for evaluating the efficacy of new drugs prior to market approval, they have limitations in addressing the post-marketing re-evaluation of the safety and efficacy of traditional Chinese medicine (TCM), failing to capture comprehensive and real-world clinical application data. TCM complex interventions emphasize personalized treatment; surrogate endpoints often fail to reflect the true therapeutic effects of TCM, whereas outcome-based endpoints best demonstrate its efficacy. Due to the complexity of TCM interventions and the need for long-term follow-up of process indicators, ensuring strict adherence to randomization is difficult, and ethical as well as compliance challenges frequently arise. Furthermore, the practical value of high-level clinical evidence from RCTs is increasingly being questioned, while real-world studies (RWS) place greater emphasis on actual clinical practice.

Therefore, clinical research in Traditional Chinese Medicine (TCM) is well-suited for Real-World Studies (RWS). The greatest advantage of RWS lies in its ability to provide additional evidence on the effectiveness and safety of drugs in real-world clinical settings. Well-designed RWS can serve as a supplement to pre-market Randomized Controlled Trials (RCTs), evaluating the safety and efficacy of marketed drugs (those already deemed effective) in actual medical practice. This is precisely what is urgently needed for the post-marketing clinical re-evaluation of TCM products.

Case Studies of Real-World Study (RWS) Practices in Traditional Chinese Medicine

In 2010, Xie Yanming’s team employed Real-World Study (RWS) methods to conduct post-marketing re-evaluation research on Chinese herbal injections for snakebite. They sequentially performed real-world post-marketing re-evaluations of Danhong Injection, Shenmai Injection, Xiyanping Injection, Shenfu Injection, Dengzhan Xixin Injection, Shuxuetong Injection, Shenqi Injection, Danshen, and Kudiezi Injection. Additionally, they conducted clinical analyses on chronic obstructive pulmonary disease, insomnia, hypertension, the incidence and Traditional Chinese Medicine (TCM) syndrome characteristics of tumors, the incidence and TCM syndrome distribution of Henoch-Schönlein purpura, and medication patterns in acute pancreatitis. The research conducted by Xie Yanming’s team covers areas such as TCM pathogenesis, diagnosis and treatment patterns, syndrome characteristics, survival studies, and post-marketing re-evaluation of traditional Chinese medicines.

In 2012, Fan Junming addressed issues such as the design of real-world studies (RWS) in traditional Chinese medicine (TCM), outcome evaluation, and handling of confounding factors. He proposed for the first time the use of propensity score methods to construct a suitable research and evaluation model for assessing the clinical efficacy of TCM—the CPOE model. This model is based on four key elements: cohort studies with sufficient sample size (C) as the foundation, propensity score methods (P) as the condition, outcome measures (O) as the gold standard, and adequate control over the stratification of exposure factors (E).

In 2013, Liu Baoyan provided a systematic exposition on real-world clinical research in Traditional Chinese Medicine (TCM). Addressing the design principle in current TCM clinical research that simplifies and idealizes complex issues to prove "causal relationships," he discussed how to understand the methodology of real-world TCM clinical research. He proposed that "from clinical practice, back to clinical practice" is the fundamental model for the development of real-world TCM. The integration of clinical practice and scientific research is the primary form of inheritance and innovation in real-world TCM, as well as the core of the TCM clinical research paradigm. "Data-driven" approaches constitute the prerequisite and technical key to the real-world TCM research paradigm.

The Big Data Era Promotes Real-World Studies (RWS) in Traditional Chinese Medicine

In the era of big data, scientific computing has become a powerful tool. Historically, Western medicine has focused more on clinical practice, making it difficult for Traditional Chinese Medicine (TCM) to gain acceptance in the West due to fundamentally different perspectives and modes of thinking. TCM’s emphasis on correlations, as well as its principles of Yin-Yang and the Five Elements, align with the Real-World Study (RWS) model of the big data era, which prioritizes correlations over precise causal relationships. Instead, it focuses on complex, multifactorial relationships. Such complexity is central to TCM’s understanding of etiology, particularly how disruptions in balance and harmony arise from changes in the body and its interaction with the environment.

Therefore, the big data era, characterized by the application of computer, internet, and data mining technologies, has made Real-World Studies (RWS) of complex relationships in Traditional Chinese Medicine (TCM) possible. This era presents both opportunities and challenges for clinical RWS in TCM. Introducing RWS into TCM scientific research represents a novel direction. In particular, the advent of the big data era provides an opportunity to integrate empirical medicine with evidence-based medicine. This approach preserves the distinctive characteristics of TCM while maintaining scientific rigor in TCM research, yielding findings that reflect real-world clinical practice. Such efforts facilitate the recognition of TCM by Western medicine, thereby promoting its global adoption.

Although Real-World Studies (RWS) represent a novel approach to the re-evaluation of therapeutic interventions, further ensuring drug efficacy and safety, they are not without limitations. RWS currently faces several challenges: with its focus shifting from drugs to patients, are pharmaceutical companies willing to invest? RWS requires large sample sizes, often involving multi-center events, making data collection difficult, labor-intensive, and costly. The high heterogeneity of data demands more sophisticated statistical methods than traditional studies. Furthermore, as most RWS are retrospective or post-hoc analyses, the level of evidence is often challenged. Addressing these issues requires collective reflection and collaborative efforts to advance the development of RWS.