Breakthroughs in data extraction and analysis coupled with federal infrastructure upgrades to handle an impending “tsunami of data” offer a promising prognosis for the future of real-world evidence (RWE) in regulatory decision-making, according to the 8th Annual Blueprint for Breakthrough Forum, hosted by Friends of Cancer Research (Friends) and Alexandria Real Estate Equities, Inc. on September 18.

Aetion was among key stakeholder organizations that attended the daylong, oncology-focused forum to advance RWE standards.

In separate keynotes, both Ned Sharpless, M.D., U.S. Food and Drug Administration (FDA) acting commissioner, and Amy Abernethy M.D., Ph.D., FDA principal deputy commissioner, alluded to a looming data barrage — in the form of RWE and otherwise — with Dr. Abernethy later outlining agency readiness plans. 

The day’s debates about operationalizing and validating the use of real-world data (RWD), and about the future of RWE, were sparked by preliminary findings from Friends’ RWE Pilot 2.0, presented by Jeff Allen Ph.D., Friends president and CEO. 

In Pilot 2.0, ten health care database vendors partnered to extract similar patient populations with advanced non-small cell lung cancer (aNSCLC) in their own data set. Aetion supported Pilot 2.0 through aggregating RWD analyses across participant data sets, and supported overall methodological determinations. The participating stakeholder organizations identified trends in clinical care such as the possibility of providing insights into effectiveness in patient populations not represented in clinical trials.

Four themes emerged from Friends’ oncology-focused forum:

1. The FDA is using RWE beyond safety.
Characterizing the moment as “a hopeful time in cancer research,” Dr. Sharpless noted the use of RWE in regulatory decisions to support expanded indication approval of Pfizer’s IBRANCE® (palbociclib) for male breast cancer, based on RWD.

Aetion President and Chief Science Officer Jeremy Rassen, Sc.D., referenced the use of RWE to secure primary approval of Amgen’s BLYNCYTO® (blinatumomab) in acute lymphoblastic leukemia. 

Along with notable progress in effectiveness determinations, RWE’s role in safety decisions continues to elevate. The post-market safety database for IBRANCE supported FDA’s decision-making on the expanded indication. 

Offering a non-oncology safety example, Dr. Rassen pointed to an RWE predictive study by the FDA that used electronic claims data to anticipate findings from the ongoing CAROLINA® clinical trial for diabetes patients. The RWE study concluded in 16 weeks, versus the eight-year-long phase IV cardiovascular outcomes trial, saving time and resources, Dr. Rassen said.

The predictive study is part of the RCT DUPLICATE project that Jacqueline Corrigan-Curay, J.D., M.D., director of the Office of Medical Policy within the FDA’s Center for Drug Evaluation and Research, noted during her panel. The partnership between Aetion, the FDA, Brigham and Women's Hospital, and Harvard Medical School attempts to use RWE from claims data to replicate the results of 30 completed randomized controlled trials, and predict the results of seven prospective trials.

2. The FDA will modernize its technical infrastructure to gird for "data tsunami."
Dr. Abernethy announced the launch of the Technology Modernization Action Plan (TMAP) at the Friends forum. The three-pronged TMAP is designed to upgrade FDA technical infrastructure to enhance data exchange, facilitate problem-solving, and engage data and technology stakeholder organizations. 

“We need to bring data into FDA efficiently and handle it efficiently, while maintaining patient privacy, confidentiality, and security. These are all realities of working with RWE,” Dr. Abernethy said.

The FDA’s Oncology Center of Excellence Real-Time Oncology Review (RTOR) project is another example of advancing FDA technical capability and efficiency by enabling real-time data flow, she said. “We are trying to do this in different pockets and scale it across other areas.”

3. Pilot 2.0 highlights RWE challenges.
Along with RWE advances, Pilot 2.0 results also reinforced multiple RWE concerns, including data quality and “missingness” (gaps in mortality data, for example); heterogeneity of patients and data sources (electronic health records versus claims versus structured and unstructured data); a lack of unified measures and variable definitions; and inconsistencies among provider methodologies. 

Yet, the concerns are not exclusive to RWE, noted Sean Khozin, M.D., M.P.H.,associate director of the FDA Oncology Center of Excellence. “Every clinical trial experiences issues with data quality and missingness,” he said. “We know data quality is a major issue, but what do we mean by data quality, and what is the acceptable threshold for decisions?”

Aetion’s Dr. Rassen cautioned against placing too much focus on data quality. “The quality of analytics is critical,” he said. “We need to think of RWE in a way similar to the execution of the controlled trial.” RWE generated using principled database epidemiology addresses data validity, data availability, and controlling for founding, which can enable the production of clinically meaningful results in RWD analyses.

4. RWE has significant potential for regulatory and payer decisions, and for patients.
For patients, RWE can include subgroups who were ineligible for controlled trials, said Wendy S. Rubinstein, M.D., Ph.D., CancerLinQ Division Director, Clinical Data Management and Curation. 

“RWE is important to me as a patient because I could not find the disease behavior in RCTs similar to my case,” said patient advocate Christie Mangir. Real-world evidence can also support other critical considerations not illuminated in controlled trials, such as productivity and financial toxicity, she added.

A steep and worthwhile climb
Up next, Pilot 2.0 data partners will further refine project protocols and more exhaustively analyze data. Acknowledging both the demanding and vital nature of the endeavor, the forum’s keynote speakers pointed to what’s next.

Dr. Abernethy lauded Pilot 2.0 participants and results and acknowledged the hurdles ahead. “RWE is hard,” she said. “If we don’t acknowledge that difficulty, and don’t fully understand and manage the data sets, uses, applications, and quality issues, we are never going to get to the place where RWE is a true complementary data set and evidence basis.”

“RWE is already here,” said Dr. Sharpless. “It’s not enough to ask what we are going to do about RWE today, but also, where should we be in ten years? The cost of clinical trials is so great. You really have no choice with a disease as heterogeneous as cancer.”