Randomized controlled trials (RCTs) are considered as the gold standard for drugs approval, before using them in the actual clinical practice. RCTs are expensive, tedious, and long- lasting with rigid inclusion criteria. These trials are associated with selection and design bias and are only useful to fast-track the oncology drug approval for a small patient population. Also, recruiting patients for a control group in trials with no effective standard care is unethical (1). As a result, the usability of the RCTs as the highest level of evidence may be reconsidered. With the rising cancer burden and changing patterns in its clinical management, there is a necessity to expedite the treatment approval (2). The real-world evidence (RWE) may complement the RCTs by providing insights into the clinical, economic, and policy-associated queries. RWE is constructed based on electronic medical records (EMR), clinics, surveys, and cancer registries (3) and is further obtained from the observational data during routine practice. The 21st Century Cures Act provided a way for RWE to be a part of the drug-labeling process. The U.S. Food and Drug Administration (US-FDA) has also proposed an RWE program to integrate the data in routine practice in FDA regulatory decisions. In the same light, CancerLinQ launched by ASCO has also developed a health technology system to collect data from EHRs and analyze it (4).
Examples Testifying To The Efficacy Of RWE
Efficacy of Treatments
RWE has become of paramount importance in the development of novel therapeutics. It can also provide us with longitudinal, long-term follow-ups to report the disease progression and treatment termination and is increasingly used to validate the findings of RCTs. For example, RWE findings were consistent with the clinical trials to prove that patients with advanced urothelial cancer harboring fibroblast growth factor receptor (FGFR) mutations have poor survival outcomes (5). Another study assessed the real-world data (RWD) in patients with castration-resistant prostate cancer (mCRPC) to understand the efficacy of a combination of abiraterone acetate and prednisone (AAP). The RWE proved that AAP was effective and well-tolerated in older patients even in presence of comorbidities and visceral disease (6). A study published by Blomstrand, H, et.al. analyzed the RWE for the effectiveness of the combination of gemcitabine and nab-paclitaxel (Gem/NabP) in advanced pancreatic cancer. This retrospective multicentric study assessed the RWE in locally advanced and metastatic disease and confirmed the efficacy and safety of Gem/NabP in both types of cancer (7). Another study evaluated the RWE for benefits of bevacizumab in platinum-resistant recurrent ovarian cancer Korean patient population. The efficacy of bevacizumab was consistent with that seen in the AURELIA study. However, its safety and efficacy varied with different chemotherapy regimens. This finding in the real-world setting became crucial in the decision-making of the treatment (8). Another study used RWE to understand the diagnostic-therapeutic pathway and outcomes in clinical practice of gefitinib, erlotinib, and afatinib in EGFR-mutated non-small cell lung cancer (NSCLC) patients. All three tyrosine kinase inhibitors (TKIs) had a similar median time to treatment failure (mTTF). Furthermore, the study evaluating the impact on the budget from the RWD opened avenues to use RWE in drug pricing (9). A recent RWE-based systematic review assessed the efficacy of CDK4/6 inhibitors in HR-positive and HER2-negative advanced or metastatic breast cancer. Palbociclib improved the survival outcomes in the real-world setting. The limited available RWE studies, comparing various CDK4/6 inhibitors were associated with prolonged survival outcomes (10). One more study used RWE to report clinical outcomes of cemiplimab in patients with cutaneous squamous cell carcinoma (cSCC). Cemiplimab is a PD-1 inhibitor and has received approval for the treatment of advanced cSCC. The RWE favoring cemiplimab in cSCC was non-inferior to clinical trials. Furthermore, the study determined factors affecting the response to cemiplimab (11). Another study validated the survival benefit associated with first-line avelumab in locally advanced or metastatic Merkel cell carcinoma (MCC). The study used an electronic health record (EHR) database to identify the patients (13). With the advancements and development of new drugs, immunotherapy is now being widely used in multiple malignancies. A study conducted a population-based ambispective cohort study to assess the efficacy of a humanized antibody, pembrolizumab. The RWD supported the use of pembrolizumab in the clinical management of non-small cell lung cancer (NSCLC) (14). Similarly, another study published by Feinberg et. al., elucidated the RWE supporting the efficacy and safety of lutetium Lu 177 dotatate, a radiolabeled somatostatin analog, for the treatment of somatostatin receptor-positive (SSTR-positive) gastroenteropancreatic neuroendocrine tumors (GEP NETs). Another example of RWE favored Blinatumomab for the treatment of Philadelphia chromosome negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) (15).
Identification of prognostic factors
Besides the treatment-associated application of RWE, it has been also used to identify the prognostic factors in patients with small-cell lung cancer (SCLC), an aggressive malignancy associated with a poor prognosis. With the availability of few therapeutics, it is crucial to identify prognostic factors. Prophylactic cranial irradiation (PCI) and initiative irradiation for primary and metastatic sites indicated improved OS. The RWD identified response to primary systemic therapy and aggressive radiotherapy to be prognostic for SCLC (16).
Evaluating adverse events
While it is important to understand the efficacy of the treatment, it is also essential to report the treatment-related adverse events along. A retrospective study aimed to identify immune-related adverse events (irAEs) in patients with malignant melanoma, NSCLC, gastric cancer, or RCC undergoing anti-PD-1/PD-L1 antibodies. High serum albumin levels and a history of Type I hypersensitivity reactions were determined to be the risk factors for irAEs (18). A classic example of complementing the trials was demonstrated in a study published by Liu, R. et al., in 2021. This study used a computational framework of Trial Pathfinder to analyze the effect of various criteria on cancer trial populations and outcomes in patients with advanced NSCLC. A data-driven approach, broadening the criteria showed that patients who were earlier ineligible could benefit from the treatment, thereby creating the eligibility criteria more inclusive while maintaining patient safety (19). A real-world population study compared the incidence of ONJ in patients treated with denosumab and bisphosphonates (BPs). Patients receiving denosumab had an increased risk of ONJ as compared to BPs (20). A population-based study evaluated the association between pioglitazone and bladder cancer risk. The findings showed that among the antidiabetic drugs, pioglitazone increased the risk of bladder cancer (12).
RWE In Context to Indian Healthcare Scenario
Considering the diversity of information provided by RWE, India can utilize the same across different disorders and illnesses. However, India needs to deal with multiple barriers in this process. While comparing private and government hospitals, private hospitals in India were recognized to be the secondary and tertiary service providers and most government hospitals were the basic service providers. This has impacted the development of electronic records, and registries in the country (22). Additionally, the pattern of clinical practice and clinicians’ approach towards RWE also pose a challenge. Considering the high rate of loss to follow-up and variable follow-ups in Indian patients, it is difficult to evaluate the endpoints. Also, most clinicians and institutions lack the initiation of RWE studies. As a result, it is the pharmaceutical companies who try to launch and fund these studies. However, very few studies reach the end-point, owing to high-budget and long-term investment (23). Despite the barriers, efforts are underway to develop these systems to integrate RWE. There are multiple areas wherein RWE can transform healthcare outcomes. Few of the opportunities include the identification of unmet medical needs specific to the Indian population and comparing the dosage in India and the Western world. As India is already making progress in generating data, collaboration with different partners can revolutionize Indian healthcare (22).
Roadblocks In The Way Of RWE Integration
Several challenges obstruct the utilization of RWE in drug development. The most common issues include small sample size, incomplete data, and undefined requirements for ‘regulatory-grade’ RWE. Additionally, the unknown population imbalances, confusing factors, misclassification issues, and selection bias influencing population-matching methods and outcomes may cause uncertainty in observed results (24). While RWE is complementary to the RCTs, it requires a large number of patients to validate the results. Moreover, data quality management is laborious and time-consuming. The data analysis involves subject experts, which further delays the results (25). Furthermore, acceptance of RWE depends on the transparency of the results. The paucity of universal standards, variations in quantity, quality, and approaches make it harder to implement RWE. The lack of policies and regulatory grade RWE requires collaborations and guidelines between policy-makers and the industry (24). The incomplete utilization of RWE is attributed to structural and behavioral hindrances like regulatory engagement, RWD availability and quality, and barriers to rapid RWE understanding and integration among healthcare professionals. These issues can be addressed via collaborative efforts, with regulatory agencies, RWE training, and RWE research (21).
RWE - Unfolding The Prospective Oncology Management
With the advent of personalized medicines and new therapeutics, it is vital to generate high-standard evidence. RWE can be particularly useful in rare malignancies and treatments. The development of uniform databases, linking of registries, and supportive technology will be crucial to increasing the data and research (26). High-quality data generation through artificial learning can be integrated to identify newer targets and enhance evidence (5). Finally, RWE and clinical trials, both remain critical to comparative research and health economics and outcomes research (HEOR). Refining RWE and improving the trial designs can widen the horizons of their application, which will eventually enhance cancer care (2).
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