Augmenting Single Arm Oncology and Rare Disease Trials with Real World Evidence

Applied Clinical TrialsApplied Clinical Trials-08-01-2021
Volume 30
Issue 7/8

RWE can augment, extend, or enrich the findings from clinical trials to provide valuable evidence to support the development programs for product approvals.

Across the industry, researchers are relying more and more on real world evidence (RWE) to better understand the benefits and risks of novel treatments, especially as they are used in routine care and in underrepresented populations. For regulators and researchers alike, RWE provides complementary evidence to clinical trial data, answering more questions, among a broader set of patients, and deepening the understanding of the benefits and risks of the treatments. Clinical trials remain the gold standard for gleaning a strong foundation of evidence about the safety and efficacy of medical products. But they cannot address all of the questions needed to understand the benefits and risks of treatments. In addition, there are cases where clinical trials may be challenging or not feasible to conduct, such as when there are insufficient numbers of patients or the study outcomes are too rare to measure in a trial setting. These challenges can be especially difficult in oncology, as rare and aggressive cancers are further stratified by molecular subtypes. In instances such as this, RWE can provide valuable evidence to support the development programs for product approvals.

Indeed, RWE can augment, extend, or enrich the findings from clinical trials: augment by using RWE in parallel with single arm trial data, extend follow-up by continuing to follow patients in an observational manner after the trial ends for evaluation of real world, longer-term outcomes, as well as enrich trial data with the collection of real-world endpoints. By knowing when and how to use RWE to complement trial findings, researchers can accelerate both new drug approvals and label extensions critical to oncology and rare disease treatments. Ultimately, these examples demonstrate how RWE can yield a greater totality of evidence on the benefits and risks to support the development of medical products.

Begin with thorough planning

When leveraging RWE, researchers should carefully plan the evidence strategy, and do so early on when designing their pivotal clinical trials. It is important to begin by deciding if real world data (RWD)—the healthcare data from which RWE is derived—adds value to a study design, and if so, what type of data source will be accessible and fit the purpose of the study’s goals. When working with RWD, researchers must:

  • provide transparency, ensuring that it is clear where the data came from, how it was reviewed, curated, and assembled,
  • deliver actionable evidence with credible methods and study design, and
  • include enough relevant patients and cover them over a sufficient period of follow-up time to identify an effect if one should exist.

Careful timing and preparation are required to coordinate how to obtain and leverage RWD. Investing this time early on and engaging with the regulators to align on strategy should be factored into the overall timelines. When researchers take this time to optimize the use of RWE, it can help streamline and potentially expedite development timelines down the road.

Work closely with regulators

In recent years, sponsors have increasingly included RWE in their submissions for regulatory decisions regarding approvals and label expansions of new medical products.1 In addition to leveraging RWE as an external comparator to provide complementary evidence to single-arm trials and measure safety and efficacy of treatments in routine care, sponsors have begun using RWD to measure long-term outcomes in patients long after a clinical trial has concluded.

Recent examples illustrate the ways regulators are embracing RWE, especially in instances for rare or orphan diseases, areas of significant unmet need, or where clinical trials alone cannot provide sufficient information. A recent review by Bolislis and colleagues presented 27 cases where sponsors submitted RWE to support a regulatory decision, including 17 for new drug applications and 10 for line extensions.2 For example, in the EMA submission of tisagenlecleucel for treating patients with diffuse large B-cell lymphoma, efficacy data from a pivotal single-arm, open-label trial was compared with a retrospective, real world external benchmark, demonstrating similar efficacy but longer duration of treatment effects when compared to standard of care.3 Similarly, the EMA submission for axicabtagene ciloleucel demonstrated a better response rate over standard of care among patients with relapsed or refractory diffuse large B-cell lymphoma by estimating the efficacy within an open-label, single arm trial and comparing the findings to a retrospective, real world, patient-pooled analysis.4 

Regulators will not provide guidance on the type of RWD to leverage in a study. However, these examples demonstrate how the additional evidence can support new drug product approvals and label expansions. Engaging with regulators early during the development process and sharing real world study plans can improve the likelihood that the RWE gathered in support of the study will be accepted as part of the submission down the road.

Looking forward

The FDA has signaled that they will provide formal guidance in 2021, advising pharmaceutical companies about the use of RWE to expedite the drug approval process. This guidance will include more information on when RWE can be leveraged and what approaches are sufficient to support new drug approvals and label expansions. However, pharmaceutical companies should not hesitate to incorporate RWE into their study design when it makes sense. Regulators are interested in engaging early and considering a myriad of approaches where RWE provides complementary evidence to clinical trials. Companies can consult the FDA’s framework on RWE for more information about how the agency plans to implement guidance as well as request meetings with the FDA to discuss specific approaches for medical product development.

The complementary information that RWE provides can be the catalyst for increased approvals and expansion of treatments that are desperately needed by patients with rare forms of cancer and other rare diseases. Regulators have indicated that they recognize the value of RWE. It’s incumbent upon pharmaceutical companies to similarly embrace RWE as part of their development efforts through strategic planning, shrewd study design and close collaboration with regulators.

Jennifer Christian, PhD, is the VP of Clinical Evidence & Epidemiology, IQVIA


  1. Rivera D, Lee JJ, Royce ME, Kluetz PG. FDA oncology center of excellence landscape analysis of real-world data submissions for oncology drugs. JCO 2021; 39(15_suppl).
  2. Bolislis WR, Fay M, Kuhler TC. Use of real-world data for new drug applications and line extensions. Clin Ther 2020; 42(5): 926 – 38.
  3. European Medicines Agency. Kymriah Assessment Report. EMA, 2018 ([EMA website]. Available at: Date accessed: June 10, 2021.
  4. European Medicines Agency. Yescarta Assessment Report. EMA, 2018. Available at: Date accessed: June 10, 2021.
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