Amy K. O’Sullivan: Challenges and Opportunities in Studying Rare Cancers

“In oncology, the shift to biomarker-defined subtypes has important implications for drug development and patient care. Whereas, in the past, large patient populations were merely defined by tumor type, they are now much smaller, further categorized by a specific biomarker – or biomarkers – within the tumor. Looking beyond the clinical implications of this shift, there are significant implications for research as well.

Within oncology research, there is an increasing desire to generate not just clinical data, but real-world evidence (RWE) on outcomes and costs in narrow or more rare patient populations, as novel targets are being discovered and more and more drugs are being approved for use in patients with specific biomarkers. There is a need to understand the real-world outcomes for these patients and how they might differ from those without the biomarker.

However, identification of patients with a specific biomarker is not easy to do in large data sets, and studying patients with rare subtypes is not always straightforward, as it comes with challenges of smaller patient populations and sample sizes thereby impacting the ability to make statistical inferences.

Interventional studies, executed according to specific protocols that dictate a specific patient population, pre-determined monitoring schedules, dosing and endpoints, may not be representative of the true patient experience in real-world clinical settings. While the U.S. Food and Drug Administration (FDA) mandates well-controlled interventional trials be the basis for new drug approvals, there is recognition that this is not enough when it comes to understanding how new medicines perform in wider patient populations.

A seismic shift occurred in 2016, when Congress passed the 21st Century Cures Act. The Cures Act was designed to help accelerate product development and bring innovations to patients faster and more efficiently. In response to the Cures Act, the FDA created a framework for evaluating the use of RWE to help support regulatory approvals of new indications for previously approved drugs or to satisfy drug post-approval study requirements.

Since then, the FDA’s Center for Drug Evaluation and Research (CDER) has published seven draft guidance documents concerning the use of RWE to support drug and biological product approvals. Despite the number of guidance documents published, examples of RWE used for regulatory purposes are few and far between.

However, there exists a range of study types leveraging real-world data that can inform life sciences companies and regulatory agencies on the use and outcomes of targeted therapies in real-world settings, including external control arm studies, registry and claims data analyses and patient surveys, among others.

This shift to biomarker-defined cancer subtypes has opened new avenues for targeted therapies but also presents significant research challenges, particularly in rare cancers and in the context of precision medicine and biomarker-driven oncology.

Challenges and opportunities can be categorized into the following four key areas:

Clinical Development

Identifying patients with specific biomarkers for recruitment and enrollment in clinical trials can be challenging and time consuming. The small size of these patient populations may reduce the generalizability of findings and the statistical power of studies, making reliable inferences difficult. Further, legal and ethical considerations, such as privacy, data sharing and informed consent, may present significant barriers, particularly in the use of genomic data.

Conversely, this research supports identification of specific genetic biomarkers associated with a disease that, in turn, can enable the development of targeted therapies designed for individuals with specific biomarkers, ideally resulting in potentially more effective treatments and improved patient outcomes. Clinical trials also can become more precise by improving patient selection, increasing the likelihood of better treatment responses, enabling early detection of disease and, perhaps, decreasing the time to market for these therapies.

Cancer Screening and Early Diagnosis

Although we have seen much innovation in biomarker detection, access to advanced comprehensive genomic testing may be limited, especially in certain geographic areas or subpopulations, which can lead to inequities in early cancer diagnosis and treatment. Further, genomic testing is costly and may not always be reimbursed, which further limits broad access to this important screening tool.

Where available, genomic testing allows for identification of specific biomarkers for early-stage cancers, leading to early detection and timely intervention, including initiation of targeted therapy. Targeted screening strategies also can assess an individual’s genetic predisposition to developing certain types of cancer, as well as to identify individuals who may benefit from targeted prevention strategies. The emergence of liquid biopsies, a non-invasive, repeatable method for cancer screening and monitoring, holds promise to make easier screening available regardless of geography or socioeconomic status.

Treatment Selection

Targeted treatment selection is only possible if the patient has been tested for specific biomarkers. Precision medicine allows physicians to select therapies that are more likely to be effective for a particular patient, leading to better outcomes. It also enables the identification of specific subgroups who are more likely to respond to a particular treatment, thereby avoiding unnecessary treatments.

Not all cancers currently have actionable targets or biomarkers that can guide treatment decisions, meaning that advanced targeted therapies may not be available or prescribed to these patients. This may change as research is used to continue to identify new biomarkers and targets for intervention. Even if actionable targets or biomarkers exist for a specific tumor type, targeted treatment selection is only possible if the patient is tested for them.

Precision medicine allows physicians to select therapies that are more likely to be effective for a particular patient and enable the identification of specific subgroups more likely to respond to a particular therapy – or combination therapy that targets multiple pathways or targets simultaneously – helping to avoid unnecessary treatments and potentially leading to better outcomes.

Treatment Outcomes

Tumors can be genetically heterogeneous, and targeting a single mutation may not be sufficient to eradicate all tumor cells. Furthermore, despite initial responses to targeted therapies, it is not uncommon for cancers to develop resistance to these therapies over time, necessitating research to identify new therapeutic targets and combinations.

Precision medicine has shown to improve overall patient outcomes relative to standards of care like chemotherapy, and there is a compelling case to be made for its continued development and integration into oncology clinical practice.

In my role as Chief Research Officer at Ontada, I lead teams responsible for the delivery of real-world research, innovative data solutions, and precise, evidence-based insights with a goal of accelerating drug development. Ontada has one of the largest community-based oncology data sets in the world, and these data, particularly the biomarker data, hold incredible promise for researchers looking to explore the long-term outcomes of precision medicine and emerging therapies.

This is an exciting time in oncology, where the acceleration of technology, data platforms and advanced analytic methods are coming together to transform the cancer landscape, from diagnosis and treatment through survivorship. The tools now available to clinicians and researchers will help them get even more precise insights regarding the right treatment for the right patient at the right time.”

written by Amy K. O’Sullivan
SVP and Chief Scientific Officer at Ontada

Amy O’Sullivan is the Senior Vice President and Chief Scientific Officer at Ontada and serves as a Board Member for ISPOR—The Professional Society for Health Economics and Outcomes Research. She is a former President of the ISPOR Boston Regional Chapter. With experience in global health economics and outcomes research (HEOR), she conducts studies to demonstrate the value of medicines and develops strategies to secure reimbursement and improve access across the Americas, Europe, and Asia-Pacific.