While randomized controlled trials represent the gold standard approach to change practice patterns and standards of care, patients enrolled in these studies do not represent the majority of patients seen in clinical practice. Patients seen in the real world are often older, of nonminority ethnic background, have comorbidities, and lack adequate psychosocial support. Furthermore, less than 5% of adult cancer patients in the United States are enrolled in clinical trials, meaning that almost 95% of cancer patients are treated in the real world. The 21st Century Cures Act attempts to address the need to understand outcomes of real-world treated patients through the incorporation of real-world evidence (RWE) into the drug-labeling process. It also suggests that observational studies are critical in the approval process, even for new indications. Much has been written in recent years about the advantages and challenges of RWE studies, and how best to utilize the data generated, moving forward.
To help us better understand the process and to shed some light on RWE studies, we caught up with Dr. Anthony Mato, Associate Attending and CLL Program Director at the Memorial Sloan Kettering Cancer Center in New York. The following are excerpts from my one-on-one conversation.
Chadi Nabhan: Why do you believe RWE studies are needed?
Anthony Mato: RWE studies are needed because there may be differences between patients who participate in clinical trials and those who are treated in clinical practice. These studies can help us to better understand the generalizability of clinical trial results to a community setting. In addition, these studies can help to answer questions that have not been addressed in current clinical trials, including expanded indications from label, toxicity profile, adherence, and unique head-to-head comparisons.
CN: How do you identify the best datasets to conduct RWE studies?
AM: The key to conducting RWE studies is to identify a dataset that accurately represents the patient population and has enough detail to answer the research questions of interest. These data can be available from administrative claims data, prospective registries, electronic health records, and retrospective cohort studies. Each of these approaches has clear advantages and disadvantages. Our approach has been to compile detailed patient-level data retrospectively from a network of academic and community sites with the main advantage of obtaining comprehensive data to answer key research questions in a timely manner.
CN: What are the advantages and disadvantages, or pitfalls, of conducting RWE studies?
AM: First, real-world studies should not be viewed as something that will replace a clinical trial. Real-world studies historically serve a different purpose, although that purpose is evolving with the passage of the 21st Century Cures Act. The major limitations of real-world studies is that they are often retrospective, some data may be missing, and patient-reported outcomes and toxicity data may not be able to be confirmed. Moreover, while it can be a strength, which I’ll get to, the fact that data are collected from many sites and the provision of care at those sites cannot be controlled like in a clinical trial, there is the potential for unmeasured confounding of the results, making it difficult to establish causation between a treatment and its effects.
Finally, inherent to the retrospective nature, the follow-up on patients may be variable both in time and place. You can’t be sure that the events of interest will have occurred, and patients may be followed at disparate intervals depending upon the provider as opposed to a clinical trial where follow-up is prespecified.
That being said, what is the place and advantage of real-world research? Traditionally, from the manufacturer perspective they have been used to build evidence for payers and to collect data for supporting formulary decision making from a cost perspective. Real-world data has been viewed by clinicians with a skeptical eye owing the inherent biases due to their nonrandom, retrospective design (in most cases). In addition, the datasets used traditionally have lacked deep clinical detail for the estimation of outcomes beyond items such as costs of care. With the advent of EMR technology we all realized that there is data which is collected through routine clinical practices that can fill some, but not all of these gaps. With the limitations of these data their strengths lay in several areas.
First, conducting real-world research is typically less expensive and time consuming. Whether using existing data or collecting primary data because care is delivered in the routine setting without an intervention, there is less risk to the patient, oversight by regulators, and the need for detailed assessments performed at specified intervals.
Second, providers will choose the treatment for a patient which is the best fit for that patient. In that case, real-world data is much more powerful in understanding the outcomes of patients in diverse settings and in populations of patients not evaluated in the clinical trial. This also allows you to study questions not answered in clinical trials potentially to inform future trial design.
Finally, clinical trials are often conducted in academic settings where the type of care delivered is differently than that given in a community practice. As a result, real-world evidence can shed light on how the process of care delivery in the real world affects outcomes for patients.
CN: Why do you believe there is an increased emphasis on RWE now versus several years ago?
AM: The field of oncology has changed dramatically in recent years with many new agents coming to the markets which have changed the treatment paradigm. In CLL, four oral targeted therapies were approved and brought to market in 2014; several more approvals are likely to occur in the next 1-2 years. With this, clinical trials have been insufficient to address all the needed questions to inform clinical practice. In particular, clinical trials have been unable to address questions related to sequencing of these agents. RWE studies may also help to refine the toxicity profile of approved agents. For example, in CLL, we identified pneumonitis as a unique unreported toxicity of the BTK inhibitor, ibrutinib, in our retrospective RWE cohort studies.
CN: Tell us about CORE and how it started.
AM: In collaboration with you, the Cardinal Health team, and other investigators across the United States, we have developed a grassroots network of centers that have committed to sharing data to answer key questions in CLL. This has led to several presentations at national meetings and publications in high-impact journals that have helped to shape the field and inform clinical practice. We have partnered with AbbVie to expand upon this ongoing effort and have called this study the CORE Study (CLL Collaborative Study Of Real-World Evidence). I believe that similar efforts could be done for other disease states and this is just one example on how we are attempting to answer RWE questions in the field of CLL.
CN: Any suggestions on how to engage community oncologists in RWE studies?
AM: RWE datasets should be presented at meetings that are frequently attended by community oncologists and presented in journals that have a high-impact value to clinicians. In addition, large community research networks such as US Oncology and Sarah Cannon could be engaged to contribute to RWE studies. The work presented by Cardinal Health at the 59th ASH Annual Meeting & Exposition is an example of how a GPO can utilize its community network to effectively engage community sites in RWE research.
CN: What does the future look like for RWE studies?
AM: As we get more advanced in establishing and utilizing systems to collect real-world data, we will have more robust information to expand its applications and address its perceived limitations. These data have and will continue to have increasing roles with regulatory bodies, payers, pathway companies, and guideline organizations to inform key decisions.