While randomized clinical trials (RCTs) are considered the gold standard of clinical research designed to establish evidence of benefit for a medical intervention, there is growing interest in real-world data (RWD) sources, and whether rigorous analysis of this information (to create real-world evidence, RWE) could be used to replace traditional clinical trials. To investigate this claim, a study published in JAMA Network Open earlier this month found that RWD sources can be used to feasibly replicate 15% of clinical trials.
Given the huge amount of excitement around RWE for clinical research, this number seems quite small. The study authors noted, “…the findings also reinforce the caution about the promise of RWE replacing RCTs.” Based on our experience using RWE in clinical cancer research, we took a deeper look at these findings. The primary goal of incorporating RWE into clinical research isn’t to make RCTs unnecessary or irrelevant, but rather to better understand how drugs perform in broader patient groups, identify expanded applications for approved therapies, or accelerate clinical trials by creating external control groups from RWD.
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Andrew Norden Andrew Norden, MD, MPH, MBA, is a neuro-oncologist and physician executive who serves as Chief Medical Officer of OncoHealth, the leading oncology specialist dedicated to helping health plans, employers, oncologists, and patients navigate the physical, mental, and financial complexities of cancer, where he leads clinical affairs and strategy. Dr. Norden previously served as […]
RWE vs. RCT – Is the goal really RCT replication, a buzzword for RCT replacement?
In contrast to the suggestion that many media headlines have made about this study, I want to clarify that the study found 15% of recent clinical trials in general medicine could be completely replaced with RWD. This finding does not address the question of whether RWE might play some complementary role in extending, supporting, clarifying or accelerating the RCTs in question.
Given the narrowly defined question the authors set out to answer, the findings seem accurate. A critical question, though, is whether the findings are relevant. In oncology, where COTA and several other RWD-focused companies are working, the goal is rarely to replace a clinical trial. Many factors need to be in place if you’re looking to replicate the control and experimental arms of the study, including that the drug needs to be FDA-approved for a long enough period of time to measure its real-world impacts on patients. This assertion is true on face value and does not require a carefully constructed study to verify it.
The study, which did not include oncology studies, looked at 220 clinical trials. Of these, 134 (61%) evaluated interventions that in the authors’ assessments could not be obtained from EHR data. For 75 of the 134 (56%), information about the intervention could not be obtained because the intervention involved an agent that was not yet approved for use.
The next major factor that rendered a trial unable to be replicated using RWD involved indications that could not be extracted from structured EHR or claims data (62 of the 86 trials for which the intervention could be ascertained, 72%). This is also an expected finding, because so much of what matters in the EHR is recorded only in the unstructured text of physician visit notes, pathology reports, imaging reports, operative reports, nursing notes, and the narratives written by other healthcare providers such as physical therapists and social workers. This explains why companies engaged in EHR-based RWE generation in oncology have sophisticated technology-assisted efforts focused on deep curation of unstructured data. Incorporation of this information very significantly extends the potential to apply in RWE in the clinical trial setting.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
Opportunities for RWE in Clinical Research
Our own experience and that of the partners with whom we work in academia, the life sciences community, and the FDA is that we aren’t aiming to obviate the need for clinical trials. Instead, we’re trying to understand how RWE can complement RCTs or provide acceptable evidence in circumstances where RCTs are not feasible.
For example, a major and important use case for RWE involves extension of findings established in RCTs to population groups that were not represented in the clinical trials. It is well known that patients in clinical trials are healthier, wealthier, and more often white than patients in the real world, which makes it challenging to extrapolate the results of a clinical trial to the broader patient population being treated. RWE can provide actionable information by describing patterns of response and adverse events associated with the drug’s use in the general population. RWE has in fact become the primary means of assessing whether RCT findings apply in older patients, in people with multiple comorbidities, and in individuals with unique socioeconomic characteristics, and there are countless examples in the published literature.
Another scenario that is growing in importance involves the use of RWE to support granting of an expanded indication for a drug already approved in another indication on the basis of RCT data. A recent example was the approval of a drug for male breast cancer, which relied on multiple types of RWE against the backdrop of RCT data previously generated for breast cancer in women. A thorough discussion has been published and is worth reading.
A related application involves the creation of an external control group from RWD. Imagine that a new drug is being developed to target a novel mutation in patients with highly refractory solid tumors. In this case, patients are unlikely to accept randomization to an existing standard of care – which is associated with poor outcomes – and oncologists have ethical concerns about randomization because some evidence of unusual activity has been observed during a phase 1 study.
Therefore, the sponsor initiates a single-arm phase 2 study with the blessing of the FDA. In this circumstance, the control group may be selected from a robust RWD set. Robustness is important because of the requirement to match prognostic factors between the experimental group and the RWD-derived control group as closely as possible. Additionally, statistical matching approaches such as propensity score analysis must be applied to ensure that measurable prognostic factors are balanced between the two arms. This unique approach is taking on increasing importance as the availability of RWD grows, and preliminary assessments in the published literature suggest that it is highly promising. A similar approach, though not yet as widely used, involves creation of an external control group that represents a hybrid of RWD and controls from prior clinical trials. I expect this to be further developed in short order.
Finally, I believe that there is an important role for RWE in drug development, even in scenarios where regulatory approval is not a consideration. The FDA has described a number of examples in which a drug that appeared promising after a phase 2 study ultimately failed upon phase 3 assessment of efficacy. This is a potentially catastrophic situation if you consider all of the patients who were unnecessarily exposed to a promising but in fact ineffective agent, not to mention the real costs and opportunity costs of the FDA, drug sponsor, and academic investigators involved in the work. Ultimately, the use of high-quality external controls derived from contemporaneous RWD has the potential to help sponsors make much better-informed go/no-go decisions as they consider whether to take a candidate drug into a phase 3 trial.
To conclude, I agree with the authors of the JAMA Network Open study that there are a limited number of situations in which RWE can completely replace a published clinical trial. The much bigger opportunity and benefit to patients is coming from the use of RWE to complement existing clinical trials and provide high-quality evidence in scenarios in which clinical trials are not feasible. Applied in this manner, RWE can benefit the patients who need access to these medications, while ultimately reducing the cost of bringing valuable new drugs to market.
Photo: metamorworks, Getty Images
Andrew Norden, MD, MPH, MBA, is a neuro-oncologist and physician executive who serves as Chief Medical Officer of OncoHealth, the leading oncology specialist dedicated to helping health plans, employers, oncologists, and patients navigate the physical, mental, and financial complexities of cancer, where he leads clinical affairs and strategy. Dr. Norden previously served as Chief Medical Officer of COTA and Deputy Chief Health Officer and lead physician for oncology and genomics at IBM Watson Health. He is the author of more than 65 peer-reviewed papers, an Associate Editor of JCO-Clinical Cancer Informatics, and an active member of ASCO and the Society for Neuro-Oncology.
