As the therapeutic paradigm for oncology moves toward targeted therapies, drug development has also undergone a shift toward advancing precision medicine in specific patient populations. In parallel, the exponential growth of computing technology and the widespread availability of electronic health data have permitted real-world data (RWD) to play an ever-increasing role in advancing cancer research and bringing therapies to patients who need them, especially in rare cancers with high unmet need.
The March 2020 OncLive® article “Real-World Evidence Should Be Part of Clinical Trials in Oncology,” by Sarah Alwardt, PhD, was a call to action for the industry to rethink how we gather data on the day-to-day usefulness of drugs for regulatory decisions.1 In this article, we will discuss how a growing acceptance of the value of real-world evidence (RWE) has led to its expanded use in oncology and explore opportunities for RWE to support drug development and regulatory decisions moving forward.
What is RWE?
According to FDA definitions, RWD relate to patient health status, or the delivery of health care routinely collected from a variety of sources, including electronic health records (EHR), billing and claims databases, and disease registries. RWE is the clinical evidence regarding the usage and potential benefits, or risks, of a medical product derived from analysis of RWD.2
RWE complements clinical trials by capturing data on the day-to-day use of drugs and can be used to support both regulatory and policy decisions. Although randomized control trials (RCT) remain the gold standard for evaluating drug safety and efficacy, they are expensive, time-consuming, and often conducted among relatively homogenous patient populations, limiting their generalizability to broader patient populations. Further, the homogeneity of RCT populations may exacerbate health disparities as diverse patients are relatively underrepresented in RCTs.
With the ability to track more patients over a longer period, real-world studies complement clinical trials by providing actionable insight into how treatments perform in clinical practice. The FDA is predicting that greater use of RWE will result in safety and efficacy information becoming available sooner in the postmarketing setting and help to further inform regulatory decisions.3
Expanding Role of RWE
The 21st Century Cures Act, enacted in 2016, requires the FDA to develop a framework for evaluating RWE in the context of drug regulation including to support the approval of new agents and new indications for previously approved drugs, and to support post-approval study requirements.4
In September 2021, the FDA published the fourth of a series of industry guidance documents in response to the Cures Act mandate, titled “Real-World Data: Assessing Electronic Health Records (EHRs) and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products.”5 This document is important for drug innovators because it reflects the FDA’s stance on how to narrow the gap between the methodological rigor of conducting RCTs vs using RWE data for the purposes of generating evidence to support regulatory submissions.
Augmenting Clinical Data with RWE
In RCTs, a control group demonstrates outcomes for patients with similar characteristics but who do not receive the experimental treatment. External controls, also known as synthetic controls, use an external data source to provide a patient cohort that can be compared against an interventional therapy.
External control groups serve the same function as traditional control arms but can be used in settings where randomization is infeasible or impractical.6-8 For example, in rare cancers, it can be difficult to obtain sufficient patient numbers for a traditional control arm. According to the FDA, external control arms could help augment new clinical data by allowing biopharma sponsors to reduce the number of patients assigned to the control arm in a randomized trial, or to conduct smaller randomized trials.9
Using external controls to evaluate the ongoing performance of drugs in clinical practice provides the ability to identify longer-term benefits as well as adverse events that might not occur during the trial period. This better informs benefit-risk assessments that can be used to support regulatory decisions, demonstrate value, aid in reimbursement, and develop treatment practice strategies and guidelines.
Following are 3 examples of how using RWD have improved our understanding and treatment of patients with cancer.
First FDA Approval of a First-line Therapy for Merkel Cell Carcinoma
APPROACH: Clinical trial eligibility criteria was applied to a real-world setting and identified patients in EHR to serve as a historical control.10
SUMMARY: Metastatic Merkel cell carcinoma (mMCC) is an uncommon yet aggressive skin cancer. Despite incidence of mMCC dramatically increasing in past 20 years, development of an evidence-based standard therapeutic regimen was lagging. However, with a small patient population and short survival times, performing a traditional RCT was not feasible. In a study performed through The US Oncology Network, using Ontada’s iKnowMed oncology EHR, a substantial patient population diagnosed and treated for mMCC was identified. Response and duration were determined using RECIST 1.1 criteria for evaluating image study reports. These data were used as a comparator for the sponsored phase 2 study evaluating avelumab (Bavencio).
RESULTS: By using EHR data, investigators were able to conduct a real-world retrospective analysis of historical treatment therapy responses. These results were used in the interpretation of the outcomes from a single-arm clinical trial that suggested that immune checkpoint inhibitors improve treatment outcomes for patients with mMCC. These results helped to establish the f irst FDA approval of a first-line therapy for this patient population.10
Supportive Data for Daratumumab Split First Dose for Patients With Multiple Myeloma
APPROACH: The aim of this retrospective observational cohort study was to provide real-world insight into the MM patient population receiving daratumumab (Darzalex) in the community oncology setting and compare the infusion time and safety associated with split first dose.11
SUMMARY: Daratumumab, a human immunoglobulin G kappa monoclonal antibody, is approved for the treatment of patients with multiple myeloma (MM). However, 46% of patients experienced an infusion-related reaction during the initial infusion. To mitigate this risk, the first daratumumab infusion was administered more slowly than subsequent infusions, with a median infusion duration of greater than 7 hours.12 To make the first infusion duration more manageable, The US Oncology Network developed a split-dose schedule to administer the first infusion over 2 consecutive days.
RESULTS: Real-world evidence demonstrated comparable safety and efficacy of the administration of daratumumab as a single 8-hour infusion of the drug vs two 4-hour infusions over 2 days. There were no statistically significant differences in reactions between groups. Although the total administration time was longer among patients receiving a split first dose, the 2-day schedule with a shorter infusion schedule offers a viable treatment option for outpatient treatment.11
Confirmed Results of Breast Cancer Therapy in Real-World Setting
APPROACH: The purpose of this retrospective, observational study was to investigate the clinical use of pertuzumab (Perjeta) in a population of patients with HER2-positive metastatic breast cancer (mBC) treated in a real-world community oncology practice setting.13
SUMMARY: Pertuzumab (Perjeta), a humanized monoclonal antibody that binds to the extracellular domain of HER2, is approved for use in the firstline setting for patients with HER2-positive mBC based on findings from the pivotal CLEOPATRA (NCT00567190) trial. Results demonstrated that the addition of pertuzumab to standard therapy improved patient outcomes in this setting.
RESULTS: The safety and progression-free survival (PFS) associated with the addition of pertuzumab to standard therapy in the first-line setting in the real-world setting were consistent with those observed in the CLEOPATRA trial. The ability to confirm results of a randomized trial in real clinical practice increases confidence in the benefits of such intervention.13
Expanding Opportunities for RWE in Oncology
The FDA has accepted RWE to monitor and evaluate the safety of drugs in postmarket studies and there is growing acceptance of the value of using RWE to support pre- and postapproval regulatory submissions. Ultimately, the goal of incorporating RWE into clinical research is to improve our understanding of how drugs perform in broader patient groups and to streamline and accelerate the clinical trial and drug development processes to bring breakthrough treatments to patients who need them.
As robust, highly accurate RWD sources continue to be accepted as valid and reliable data sets, the more we hope they will be used in RWE and external control studies to support a variety of regulatory decisions, including the following:
Clinical Trial Design for Unmet Needs
RWE has been proven effective at helping generate hypotheses for testing in RCTs, identifying drug development tools (including biomarker identification), assessing trial design, and assembling external cohorts for uncommon disease subsets.2 Incorporation of RWE has the potential to improve the recruitment of patients as well as speed the development process for new oncology drugs and make them available to patients earlier.
Complement Single-Arm Trial Design
In single-arm trials, the use of external control data can potentially support the development of comparative benchmarks, especially for conditions with high unmet need. If preliminary clinical evidence for an anticancer agent in a single-arm trial suggests a substantial treatment effect, evaluating outcomes in similar groups of patients using RWD may provide a reliable assessment of the safety and effectiveness for comparison. Oncology agents with a breakthrough therapy designation program are especially appropriate candidates for the use of RWD to support regulatory decisions.2
Confirmation of RCT Results
The ability to use external controls to replicate and confirm the results of RCTs in clinical practice expands the clinical data associated with a treatment option and increases confidence in the benefits of that intervention.2
Oncology therapies approved for a specific indication are frequently used for the treatment of related malignancies. RWE may rigorously document safety and effectiveness with the level of quality and detail needed to support label expansion. Using high-quality RWE to secure broader indications can accelerate access to patients, as well as reduce the costs associated with RCTs.2
RWE is playing an increasingly important role in oncology where treatment decisions are affected by histology of disease and for uncommon conditions for which there are no approved treatments or treatments with only conditional approvals. When used as supportive data, RWE can influence drug development and inform regulatory approvals of breakthrough medicines designed to identify unmet needs and improve patient care. By offering value throughout the drug development cycle, RWE can help biopharma companies shorten development time, reduce the cost of clinical trials, inform clinical practice, and clarify the value of new therapies.
- Alwardt S. Real-world evidence should be a part of clinical trials in oncology. OncLive®. March 28, 2022. Accessed June 20, 2022. bit.ly/3y7Pj5C
- Framework for FDA’s real world evidence program. FDA. December 2018. Accessed June 20, 2022. bit.ly/3OuwPld
- Statement from FDA Commissioner Scott Gottlieb, MD, on FDA’s new strategic framework to advance use of real-world evidence to support development of drugs and biologics. News release. FDA. December 06, 2018. Accessed June 20, 2022. bit.ly/3bkA8gs
- 21st Century Cures Act. FDA. Updated January 31, 2020. Accessed June 20, 2022. bit.ly/3QAioOt
- Real-world data: assessing electronic health records and medical claims data to support regulatory decision-making for drug and biological products. FDA. Updated December 10, 2021. Accessed June 20, 2022. bit.ly/3xNhtS2
- Thorlund K, Dron L, Park JJH, Mills EJ. Synthetic and external controls in clinical trials – a primer for researchers. Clin Epidemiol. 2020;12:457-467. doi:10.2147/CLEP.S242097
- Hatswell AJ, Baio G, Berlin JA, Irs A, Freemantle N. Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999-2014. BMJ Open. 2016;6(6):e011666. doi:10.1136/bmjopen-2016-011666
- Baumfeld Andre E, Reynolds
- R, Caubel P, Azoulay L, Dreyer NA. Trial designs using real-world data: the changing landscape of the regulatory process. Pharmacoepidemiol Drug Saf. 2020;29(10):1201-1212. doi:10.1002/pds.4932
- Beckers F, Capra W, Cassidy A, et al; Friends of Cancer Research Working Group. Characterizing the use of external controls for augmenting randomized control arms and confirming benefit. Presented at: Friends of Cancer Research Annual Meeting 2019. November 12, 2019; Washington, DC. Accessed June 20, 2022. bit.ly/3b6H8gY
- Cowey CL, Mahnke L, Espirito J, Helwig C, Oksen D, Bharmal M. Real-world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA. Future Oncol. 2017;13(19):1699-1710. doi:10.2217/fon-2017-0187
- Rifkin R, Singer D, Aguilar KM, Baidoo B, Maiese EM. Daratumumab split first versus single dosing schedule among patients with multiple myeloma treated in a US community oncology setting: a retrospective observational study. Clin Ther. 2019;41(5):866-881.e7. doi:10.1016/j.clinthera.2019.03.013
- Darzalex. Prescribing Information. Janssen Biotech; 2022. Accessed June 20, 2022. bit.ly/3N9XOSb
- Robert NJ, Goertz HP, Chopra P, et al. HER2-positive metastatic breast cancer patients receiving pertuzumab in a community oncology practice setting: treatment patterns and outcomes. Drug Real World Outcomes. 2017;4(1):1-7. doi:10.1007/s40801-016-0102-5