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The use of external control arms in oncology is an evolving area that is generating increasing interest among regulators and sponsors alike. While traditional control arms in randomized trials are the mainstay of clinical research, long-running oncology trials highlight why the inclusion of a control group that receives a placebo isn’t always feasible or ethical. Rare disease research faces notoriously challenging recruitment, and no cancer patient wants to land on the placebo side of a trial when they could receive potentially life-saving treatment.
Fortunately, real world evidence (RWE) is increasingly being accepted as a mechanism to answer these challenges. Rather than populate a control arm with randomized patients from inside a trial’s recruited population, researchers can generate insights from an external comparator—a real-world cohort of patients with characteristics similar to those who are being studied in a clinical trial. This approach allows regulators to compare the safety and efficacy of new treatments to the existing standard of care, while ensuring all trial participants receive potentially beneficial options.
External control studies could be a suitable alternative to a traditional randomized trial, but there are myriad considerations to address validity issues and minimize bias. In February 2023, the U.S. Food and Drug Administration (FDA) released guidance for the use of external control arms, stating that, “the suitability of an externally controlled trial design warrants a case-by-case assessment.”1 So, how to present the strongest case? This paper will focus on key regulatory and operational considerations to give trials the best chance of success with external comparators.
The new guidance provides recommendations to sponsors and investigators, addresses considerations for the design and analysis of externally controlled trials, and describes considerations related to communicating with the FDA. IQVIA has long been at the forefront of exploring novel uses of RWE and was intimately involved with the development of this guidance through collaboration with Real World Evidence Alliance, an independent coalition of data and analytics organizations that provides input to regulatory bodies from the industry's perspective.
Key points from the guidance include:
Given these factors, there is no doubt that early planning is key to successfully using external comparators. The remainder of this paper will discuss considerations for using that planning time in the most efficient and effective way possible.
Our knowledge of cancer has dramatically improved in recent years. We now know that, despite some common hallmarks, the concept of cancer comprises multiple different diseases. Even within one specific cancer type there can be numerous subtypes differentiated by features, e.g., biomarker or gene expression, histopathological features, and clinical features. To add to the complexity, there are also geographic and race/ethnicity variations not only in the incidence and mortality of these diseases, but also in their treatment and clinical presentation.
While all this knowledge is incredibly helpful in understanding the complexity of various cancers, it also poses a challenge to the traditional clinical trial construct. Namely, a randomized controlled clinical trial will sometimes enroll only a relatively homogenous patient population, challenging its representativity and generalizability to the broader population typically seen in the clinic.
Strength: An opportunity for patient-centered, inclusive trialsThis is where external comparators offer a huge benefit; they help us reach an extended clinical population with great specificity and expand our trial to be more inclusive and reflective of the clinical situation at hand. External comparators also allow us to address treatment effects in rare tumor types and subpopulations that are not sufficiently prevalent to be represented in a statistically powerful way in a randomized controlled trial. We can even address differences in geographical regions by adapting to specific regulatory requirements particular to a given region or country, allowing our studies to reflect traditionally underrepresented populations, like minority groups.
Challenge: Variations and rapidly changing parameters in oncologyOn the other side, variations in how certain cancer markers are tested and classified, as well as rapid change in the treatment landscape, have the potential to pose challenges to external comparator validation and should be well considered upfront. For example, the use of assays and classification systems of predictive and prognostic markers may vary across geographies and institutions. The same is true for clinical drivers of therapeutic decision and safety management. With the rapidly changing oncology landscape, an external comparator started later than the randomized trial needs to acknowledge the potential for changes in clinical practice, such as the introduction of novel therapies or potential safety issues that were not established when designing the randomized trial.
When we are assessing biomarkers, we also must consider whether retrospective tissue information will suffice, or if we need to have a prospective collection of tissue, e.g., in tumors where we know that expression can change due to prior treatment. Considerations should also be made for genetic biomarker testing, where validated assays are not always available. Finally, both efficacy and safety endpoints are dependent on the quality of the source database. The choice of which endpoints to collect and how to collect them needs to be well thought through and should aim to align with both the reflected randomized clinical trial and clinically relevant outcome measures for the study treatment.
These are complex considerations, but IQVIA’s extensive experience building and executing external comparator studies has surfaced best practices to ease the process. Below are several approaches to support their successful execution:
Best practices for external comparators are still being established and debated within the scientific community, and with the FDA’s recent guidance, these will continue to take shape. With the current oncology R&D landscape focused in areas of high unmet need, external comparator studies are poised to play a key role in bringing life-changing—and potentially life-saving—treatments to patients.
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Meet your clinical, economic, and regulatory needs throughout a product's lifecycle using U.S. real world solutions.
Augment your clinical studies with a control arm from real world data to add comparative context. Generate impactful evidence to support successful market authorization and reimbursement.
Use emerging data sources and advances in evidence methods to demonstrate product value and safety.
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