Real-world evidence is becoming increasingly important in the clinical care of cancer patients. When combined with traditional clinical trial data, it can expand the breadth of robust evidence on which therapies work best for which subsets of patients because the data come from a real-world setting such as clinical practice.
That goal of expansion of relevant evidence was the genesis of a new pilot project sponsored by the Friends of Cancer Research (FOCR); the group released its initial findings on the uses of real-world data at a meeting in Washington, D.C.
The project set forth a framework to evaluate real-world endpoints in the care of advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. Before real-world data can be useful, it must be accurately abstracted. Six data sources were used for the pilot study; what was remarkable was the high level of shared characteristics among the varying datasets despite their differences. Speakers at the meeting said this finding of agreement demonstrates the feasibility of the pilot project's approach to abstracting real-world data.
What Is Real-World Data?
Real-world data, defined as clinical evidence derived from data on the uses and potential benefits and/or risks of a medical product outside of a traditional clinical trial, may include surrogate endpoints other than overall survival, such as time to progression and progression-free survival. Real-world data are derived from electronic health records (EHRs), clinical decision and support and hospital-based systems, administrative billing and claims databases, patient registries, longitudinal cohort studies, and patient-reported outcomes tools.
“We all know that a small number of patients participate in clinical trials,” said FOCR Founder and Chairperson Ellen V. Sigal, PhD. Therefore, she said, it is important to know what happens to patients outside of trials in clinical practice. The pilot project is a “first step in defining real-world data and what it means to patients,” she said.
FOCR President and CEO Jeff Allen, PhD, said the group chose NSCLC for its pilot project because there are multiple approved therapies to treat it. He said it was “quite striking” that the data points in the pilot study from the six different participating groups were so similar and so much in agreement, despite the varying sample sources, varying data capture processes, and varying data sources. “We're very interested in next steps,” he noted. “What would pilot project 2.0 look like?”
The six pilot project health care data participants included these groups:
- the Cancer Research Network, which began as an NCI-funded consortium of research groups affiliated with a dozen integrated health care systems across the U.S.;
- Cota, whose real-world evidence database is a HIPAA-compliant, de-identified data source drawn from the EHRs of contributing academic, for-profit, and community oncologist provider sites and hospital systems;
- Flatiron Health, a longitudinal, demographically diverse database derived from EHR data from more than 265 cancer clinics (some 800 sites of care);
- IQVIA, a leading global provider of information, innovative technology solutions, and contract research services;
- Mayo Clinic Analysis using OptumLabs Data Warehouse, an open, collaborative research and innovation center founded in 2013 as a partnership between Optum and Mayo Clinic; and
- PCORnet sites (the pilot project included 11 PCORnet partner sites that had previously participated in a PCORnet Rapid Cycle Project).
Data endpoints studied included overall survival, time to next treatment, time-to-treatment discontinuation, progression event, real-world progression-free survival, real-world time to progression, and index date (the earliest PD-L1 inhibitor initiation in the advanced setting anchored to start the immune checkpoint inhibitor-containing regimen [nivolumab, pembrolizumab, atezolizumab]).
In presenting the pilot project's findings, Allen said that, in addition to the remarkable agreement among the real-world data points from the six different sources, the study also accomplished the following:
- Demonstrated that several extractable endpoints from EHR and claims data correlate with overall survival, the gold standard in clinical trials. He noted that further validation is needed to determine whether these real-world endpoints are reliable surrogate endpoints for overall survival outside a traditional clinical trial, and whether they can be used to support regulatory and payer decision-making.
- Showed that survival among patients as assessed through EHR and claims data falls within the range of median overall survival values observed in several trials on immune checkpoint inhibitors.
- Showed that assessment of extracted endpoints from EHR and claims data demonstrated that efficacy of immune checkpoint inhibitors is relatively consistent across a variety of patient characteristics, such as age and sex. As to age specifically, Allen said there was a high degree of similarity in the data on patients under age 75 and those over age 75. This finding was “just remarkable to me,” said Amy Abernethy, MD, PhD, Chief Medical Officer, Chief Scientific Officer & Senior Vice President for Oncology at Flatiron Health. “We can use this observation in clinical practice.”
“I think the pilot project is a proof of principle,” said Rajeshwari Sridhara, PhD, Division Director of Biometrics V, Office of Biostatistics, which supports the Office of Hematology/Oncology Products, Center for Drug Evaluation and Research (CDER) for the FDA. “I think we're heading in the right direction” in the use of real-world evidence.
But she cautioned that “We have to be very careful in knowing what can be measured and doing it consistently.” She also noted that the FOCR pilot project is disease-specific, so it remains to be seen whether this approach would work in other diseases.
“We're very interested in getting additional data on drugs,” said Janet Woodcock, MD, Director of CDER at the FDA. Specifically, “There's just a general void in understanding quality-of-life issues in cancer care.” She noted her goal is to bring together in collaboration the clinical enterprise with the research enterprise within the flow of medical practice. “It's doable.” With that in mind, she said it is very important to have studies like the FOCR pilot and to learn from them.
“We look at real-world evidence to augment clinical trial data,” said Sean Khozin, MD, MPH, Associate Director in FDA's Oncology Center of Excellence. He noted that the FDA has evolved from passive pharmacovigilance to more active use of real-world evidence.
Incorporating real-world evidence into drug regulation is now a mandate. Passed in December 2016, the 21st Century Cures Act requires the FDA to develop a framework and issue guidance on real-world evidence to support a new indication for an already approved drug or post-market studies as a requirement for regulatory approval. FOCR noted that the FDA has already issued similar guidance on use of real-world evidence for medical devices. As previously reported in Oncology Times, FDA Commissioner Scott Gottlieb, MD, is committed to using earlier surrogate endpoints rather than overall survival in regulatory decision-making when it is appropriate, and he plans to publish these endpoints online when they are the primary basis of a drug's approval.
FOCR's written report on its pilot project notes that potential uses of real-world evidence for future pharmaceutical approvals include expanded labels, pragmatic clinical trial design, and confirming benefit in converting an accelerated approval to full-approval status. The report notes that real-world evidence could be used to “provide helpful information about the long-term value of a product and could inform future value assessments.”
Agreeing was Lawrence H. Kushi, ScD, Director of Scientific Policy in the Division of Research at Kaiser Permanente. “I think there's a great opportunity to learn from each other and have a learning health care system in the larger sense,” he noted.
Among the discussion issues raised by FOCR: What is the role of real-world evidence for payer decision-making, particularly in the context of accelerated approval or breakthrough designation? How important is real-world evidence in the development of new payment designs, such as value-based payment, risk-sharing arrangements, and outcomes-based agreements? How timely does the data have to be for regulatory review or reimbursement?
Peggy Eastman is a contributing writer.
Project Limitations & Challenges
The FOCR pilot project report notes the following limitations and challenges of the project's datasets:
- The ability to collect reliable data will vary across data providers.
- Verifying and determining the date of death often proves surprisingly challenging.
- Approaches to analysis may vary even when using a common protocol, making collaboration necessary to reach alignment on a consistent and reliable approach.
- Verified diagnosis and diagnosis date, clinical stage and cell type, planned chemotherapy regimen (dose and schedule), and other clinical and socioeconomic factors cannot always be determined from the available EHR and claims data.
- For claims-based data, some patients with advanced disease may enroll in clinical trials, and some or all the care received in a clinical trial setting may not generate insurance claims, so data for these patients may not be fully captured or captured at all.
- Some biomarkers may not be routinely assessed in the real-world setting; more would have been included in this analysis if a chart review had been conducted or if natural language processing had been employed.
- Provider data from the EHR may not identify all chemotherapy, since patients may seek care inside and outside a provider group that contributes to the EHR data (e.g., if patients move from an academic to a community setting).