FDA Draft Guidance Imminent Following ODAC’s Consideration of Real-World Data in Pediatric Oncology


On the second day of a 2-day meeting of the Pediatric Oncology Subcommittee of the FDA’s Oncologic Drug Advisory Committee, members and guests brought into question the role of real-world data in regulatory decision-making for pediatric oncology drugs.

On the second day of a 2-day meeting of the Pediatric Oncology Subcommittee of the FDA’s Oncologic Drug Advisory Committee (ODAC), members and guests brought into question the role of real-world data in regulatory decision-making for pediatric oncology drugs.

Outside of clinical trials, data collected from patients treated in clinics across the country provide real-world evidence that may fill in information gaps about oncologic drugs. In pediatric oncology, the questions raised by the committee comprised current and future resources for real-world data, the FDA framework on the use of real-world data to aid in regulatory decision-making, the limitations of these data sets, and how to understand adverse events (AEs) in real-world patient populations.

According to a presentation from the FDA given during the ODAC meeting, the use of real-world evidence to guide FDA decisions has been accepted by the regulatory body prior to the 21st Century Cures Act of 2016. The act allows the FDA to approve drugs based on real-world data and to review real-world evidence to satisfy post-approval study requirements. 

Within the FDA’s Center for Drug Evaluation and Research (CDER) exists a framework for real-world evidence, which outlines things like the FDA’s priorities for utilizing real-world evidence and its key challenges with it. Although not specific to pediatric cancers, experts believe the use of the framework to draft FDA guidelines around the use of real-world evidence in pediatric oncology is warranted. Draft guidelines are expected to be released by December 2021.

“Real-world data from children and adolescent with cancer can be obtained from multiple sources in the potential for use as well-characterized and appropriately collected in the standardized data to create sufficient evidence,” said Gregory H. Greaman, MD, associate director for Oncology Sciences at Center for Drug Evaluation and Research at the FDA, during a presentation. “It’s of particular interest in the light of the rarity of specific cancers in children. This creates issues for clinical trials designed to demonstrate the effectiveness.”

The ability of real-world evidence to show the safety and efficacy of drugs has predominantly been shown in adults. Greaman highlighted real-world evidence from lutetium Lu 177 dotatate (Luthathera) for the treatment of gastroenteropancreatic neuroendocrine tumors, and palbociclib (Ibrance) for the treatment of men with select advanced or metastatic breast cancers. Both studies were single-arm and conducted in real-world settings, which ultimately led to approvals for those indications.

Going forward, there is a belief that real-world evidence can support approvals for pediatric oncologic drug s, but this is unlikely to occur using single-arm studies. Instead, experts believe that controls will be utilized to provide comparisons that support the efficacy and safety of drugs.

Controls for Real-World Research

In creating control for real-world studies, a key challenge is interpreting time to event end points, but the FDA identifies the use of external controls as a potential solution to the problem.

“Many clinical trials of new cancer drugs are designed as single-arm studies with a plan to use the historical or external controls. Real-world evidence might also contribute to the development of priors for randomized studies incorporating adaptive designs,” said Donna R. Rivera, PharmD., MSc, during the FDA’s presentation.

Rivera explained during the presentation that many points must be brought into consideration including the use of covariates, data selection, data quality, and missing data. Moreover, all of these considerations may be limitations to the use of real-world evidence. In pediatric oncology, specifically, an important tip is to limit biased research.

Expert Discussion

Attendees at the meeting of the ODAC’s Pediatric Oncology Subcommittee appeared to support the use of real-world data in pediatric oncology for aiding regulatory decision-making. On the question of current and future resources for real-world data that can help push the effort forward, oncologists noted that understanding molecular testing is an important tool.

“One area this highlights is the rare molecularly-defined subgroup of rare pediatric cancer and [the importance] of having a well-characterized cohort of patients already identified with a specific molecular alteration. This would be incredibly helpful because that's a classic example where randomization becomes very challenging. I think in our field, it is going to be an important contribution of these initiatives to develop more real-world data,” said Steven DuBois, MD, MS, director, experimental therapeutics, and senior physician at Dana-Farber Cancer Institute Boston Children’s, during the meeting.

In agreement, Katherine A. Janeway, MD, MMSc, director of clinical genomics and senior physician at Dana-Farber Cancer Institute stated, “I think that for some of our sort of rare unmet medical needs cancers and I'm thinking about osteosarcomas. Some cancers are sort of stuck in a catch 22 in in terms of what are the limitations on our ability to create those high-quality datasets from our patients who enroll in clinical trials. In a new clinical trial for newly diagnosed osteosarcoma, for example, we have limited information about genomic subtypes that predict response or resistance to treatment. Because of that, we don't have biomarkers that we can justify performing on the clinical trial, therefore we miss the opportunity to require a sample submission on the clinical trial, and it's hard for us to identify funding to support those efforts. So, if one of the challenges in a cancer type like that is obtaining the resources, it’s both the samples and also the funding to support the endeavor to generate the types of datasets that are going to be useful in the future.”

Finally, Theodore W. Laetsch, MD, attending physician in the Cancer Center at Children's Hospital of Philadelphia made a point about patients being in different disease settings and how real-world research in the future should focus more on patients in those various settings.

“I think a number of drugs that are in development are initially at least studied in the relapsed or refractory setting. I think developing additional resources in that setting will also be important in addition to the resources looking at real-world data for newly-diagnosed patients.”


Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC). FDA. May 12, 2021. Accessed May 12, 2021. https://bit.ly/2RU9zVJ

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