Real-world evidence (RWE) has garnered increased attention in recent years as both a supplement and complement to traditional clinical trials, bridging the gap between the constraints of the trial setting and the realities of clinical practice. The 21st Century Cures Act, designed to improve the efficiency and speed of new medical product development and regulatory approval, was signed into United States (US) law in 2016.1 The Act mandated that the Food and Drug Administration (FDA) establish a program to evaluate the potential use of RWE to support the approval of new indications for drugs, as well as to satisfy post approval study requirements. This development marked a shift in thinking about RWE for regulatory purposes. While the FDA has historically relied on RWE to monitor post marketing drug safety, the use of RWE to demonstrate efficacy and safety of a drug in support of a new indication is relatively uncommon. The Framework for the FDA’s RWE Program was published in 2018, outlining 3 key factors they will consider in evaluating RWE in regulatory submissions: whether the real-world data (RWD) are fit for use (whether the clinical study methodology is acceptable and the data are reliable and relevant); whether the study design used to generate the RWE can provide adequate scientific evidence to answer the regulatory question; and whether the conduct of the study meets FDA regulatory requirements.2 In the framework document, RWD is defined as data related to patient health status and/or the delivery of health care that is routinely collected from a variety of sources, such as electronic health records (EHRs), claims and billing reports, registries, and other sources such as mobile devices. RWE is created via analysis of RWD, and provides clinical insights with respect to the usage, benefits, or risks of a medical product.
To gain insight into best practices for studies generating RWD, and to help inform the development of guidance documents, the FDA is undertaking a series of demonstration projects. These include projects to assess study designs using RWD to support efficacy, to assess data collection and data quality of RWD from multiple sources for use in regulatory decisions, and to harmonize data standards across RWD networks. RCT DUPLICATE is one such project; to provide insight into the feasibility of answering clinical efficacy questions with RWD, this project will attempt to replicate the results of 30 completed phase 3 and 4 randomized clinical trials (RCTs) with RWD from claims databases, using standardized, high-quality methodologies.3 A recent addition to this project is an attempt to predict the results of 7 ongoing phase 4 RCTs using RWD from claims databases, to gain a better understanding of circumstances under which RWE may substitute for or complement RCTs.
Although the Agency will not issue draft guidance on the use of RWE to support the approval of new drug indications until 2021, a significant precedent exists for FDA’s acceptance of RWE in regulatory submissions. For rare diseases in particular, the smaller numbers of patients available creates challenges to conducting traditional RCTs. When the disease is serious or life-threatening, the investigational drug may be eligible for accelerated approval, a circumstance under which FDA more often demonstrates flexibility and accepts single-arm trials to support approval. In this setting, historical controls to contextualize a drug’s efficacy and safety comprise the majority of cases where RWE was included in New Drug Application (NDA) or Biologics License Application (BLA) submissions.
Many cancers are rare diseases, and the increasing use of precision medicine principles to define cancers by their genome rather than organ of origin is resulting in common cancers becoming a collection of rare subtypes. The use of historical controls in NDA and BLA submissions for cancer drugs predates the Cures Act. One example is the original marketing approval of blinatumomab for relapsed or refractory, Philadelphia chromosome-negative, B-cell precursor acute lymphoblastic leukemia (ALL) in 2014.4 The single-arm trial was supported by a historical control group of data derived from chart review of 694 patients from U.S. and European study sites. More recently, in 2018 blinatumomab was approved for the indication in minimal residual disease (MRD)-positive ALL. The supplemental BLA submission included a historical comparison group of retrospective data on patients in complete response 1 or 2 with MRD-positive ALL, collected from clinical sites, to support the single-arm BLAST study.5
In addition to the use of historical controls, RWE reflecting the use of the investigational drug in clinical practice has also been employed to support FDA approval of new oncology drug indications. Some examples also predate the Cures Act: in 2016, blinatumomab was approved for the ALL indication in the pediatric population, supported in part by data from 41 children under the age of 18 in a single-arm, open-label, expanded-access protocol.6 An expanded-access study also supported the approval of lutetium-177 dotatate for somatostatin receptor-positive (SSTR-positive) gastroenteropancreatic neuroendocrine tumors in 2018; the ERASMUS investigator-sponsored, single-arm study of 1,214 patients with SSTR-positive neuroendocrine tumors retrospectively evaluated investigator-assessed efficacy and safety outcomes, and helped supplement the NETTER-1 clinical trial.7
Integrating RWE into the drug development and approval process has the potential to reduce the time, cost, and patient burden associated with clinical trials, while providing clinically relevant information to all stakeholders, but challenges remain. Small sample sizes, data quality, and methodological issues with submitted RWE were among the concerns cited by FDA reviewers in drug approval packages. In addition, submitted RWE did not meet FDA’s statutory evidence requirements in several recent oncology drug approvals, including selinexor, erdafitinib, and entrectinib.8-10 As the Agency continues to build their knowledge base and refine their understanding of the possibilities for and limitations of RWE, the requirements for “regulatory grade” RWE are likely to become more stringent. Nevertheless, it is anticipated that the proportion of regulatory submissions incorporating RWE to support approval will continue to increase, and that we will see a broader scope of RWE utilized, across a wider range of indications. With less than 5% of adult cancer patients enrolled in traditional clinical trials,11 the adoption of RWE as a credible, reliable data source for regulatory decision-making has the potential to provide representation for a much larger and more diverse patient population, while accelerating development of and access to cancer drugs.