March 2017 Edition Vol.11, Issue 3

Using Real-World Evidence in the Cancer Care Continuum

By Kathy Boltz, PhD

When it comes to cancer treatment decision making, real-world evidence (RWE) may have the potential to be a new driving force. RWE includes data gathered from electronic health records, claims and billing data, product and disease registries, and through personal devices and health applications.

Possible applications of RWE in oncology include confirming benefit for new indications to support a label expansion, optimizing clinical use to support label revisions, and meeting requirements for post-marketing information and for safety monitoring.

The expectation is that RWE will potentially generate better understanding of patient populations who are not typically studied in clinical trials.

“RWE complements traditional clinical trials and can be used in service of regulatory and clinical oncology decision making,” said Amy Abernethy, MD, Chief Medical Officer of Flatiron Health — a healthcare technology company that accumulates real-world data to accelerate research and improve cancer care. 

Generating evidence outside of clinical trials is an oncology priority for the FDA.1

“With robust real-world data sets, researchers have the ability to examine the effectiveness of approved treatments used in the off-label setting,” said Abernethy.

The data can also be used to track utilization, effectiveness, and safety in the transition from clinical trials to real-world care after regulatory approval, as well as by investigators looking to answer large-scale, complex research questions. These efforts have the potential to accelerate and improve personalized and efficient cancer care delivery, according to Abernethy.

The 21st Century Cures Act includes establishing a program within 2 years of the bill’s enactment to evaluate the potential of RWE to help support the approval of a new indication for a drug or to help support or satisfy post-approval requirements.2

The FDA must issue draft guidance on the use of RWE no later than 5 years after the bill’s enactment. The Cures Act was signed into law on December 13, 2016.

RWE is expected to become an increasingly critical element of precision molecular medicine as treatments for rare diseases proliferate. Accelerated approval programs that review these types of treatments will use RWE to allow the data on clinical benefit and value to be available more expeditiously.3

It is thought that RWE may also help to overcome the difficulties of enrolling sufficient numbers of patients in traditional randomized controlled trials in rare diseases.

 

Strict data quality and better organization needed

Concerns exist around possible flawed conclusions coming from the limitations of the source data and analytic approaches. Abernethy said, “The industry is also working to address how we can do trustworthy analyses of RWE with strict data quality and assurance standards that all constituents find credible.”

At Flatiron, they are working on new data quality and analytic frameworks to undergird credible RWE. They are also working with the FDA to make sure that the data, analytic approaches, and quality assurance methods are appropriate.

Organizing the massive amounts of information is a key challenge around RWE. Data finding is a major source of frustration and inefficiency for both providers and researchers.

“Today, our most significant challenge around the electronic health record is the need for better organization of the patient information,” said Abernethy.

One limitation that Flatiron is actively trying to solve is the ability to integrate technology platforms so they can link RWE to disparate data sources, including claims data, genomic profiling, and mortality databases.

Abernethy said that a master index does not exist, as data linkage itself is difficult, especially when patient privacy must be the priority. Efforts such as the NCI’s Genomic Data Commons and Project Data Sphere are looking to solve this, as is Flatiron Health through their partnership with Foundation Medicine.

“Over half of the important data points in EHRs [electronic health records] are embedded deep in ‘unstructured documents,’ such as doctors’ notes or radiology reports,” said Abernethy.

 

Patient advocacy groups contribute RWE

Patients also play critical roles in generating and sharing large data sets, as well as Big Data systems that are involved in RWE.

“Patient advocacy groups play an important role in helping to ensure that patients are informed and educated about the role of data sharing in research,” said Abernethy.

Because many patients and advocates may not feel comfortable or prepared to participate in Big Data without training, training programs are available for patients and advocates on how data gleaned from patients’ experiences with cancer can lead to groundbreaking research.4

Patient advocacy groups harnessing the power of patient information to create RWE for better treatments and to offer data to pharmaceutical partners for research purposes include the Pancreatic Cancer Action Network (PanCAN) and the Multiple Myeloma Research Foundation (MMRF).

“The MMRF has created the only precision medicine research model that spans the cancer ecosystem,” said Paul Giusti, CEO of the MMRF.

MMRF stakeholders include patients, academic medical centers, community cancer centers, biotech and pharmaceutical industries, technology partners (such as bioinformatics companies), and the FDA.

According to Giusti, engaging and retaining patients is key to advancing research, but many barriers exist to doing so, from a lack of understanding among patients of the value of their data to concerns about privacy and data breaches. “We have made it a priority to empower patients to be part of the research process through our CoMMpass study and Community Gateway as two examples,” said Giusti.

 

Know Your Tumor Program

Lynn Matrisian, PhD, MBA, Chief Science Officer of PanCAN explained that their Know Your Tumor personalized medicine service uses molecular profiling to help determine the best treatment options.

Patient Central Associates identify those patients who are at a point in their journey where molecular profiling is feasible and there is enough time to get and react to the results. The Associates follow up to answer any additional questions and help facilitate any actions that might be indicated because of the Know Your Tumor report, explained Matrisian.

Matrisian said that some oncologists refer their patients to the Know Your Tumor program, while others are encouraged by patients who play an active role in agreeing to the testing and with considering therapeutic options presented by the Know Your Tumor report.

The reports usually list options that are not standard-of-care, and so oncologists may have concerns about sending a patient to another institution for a clinical trial.

Additionally, requesting insurance support for off-label treatments can also be a concern for patients and providers. PanCAN has an arrangement with the Patient Advocate Foundation to provide customized case management services for patients who face problems with insurance coverage for molecularly-indicated off-label treatments.

 

Creating a culture of data sharing

“Through data-sharing practices have changed for the better, far too many academic medical centers and community cancer centers continue to hold on to and not share valuable patient data, whether it’s clinical or molecular. By creating incentives for sharing—for example, research funding, access to a large pool of high-quality data—we have continued to encourage data-sharing throughout the ecosystem,” said Giusti.

Data-sharing among some biotech and pharmaceutical companies can be similarly non-existent, he said. Partnerships among these companies, who historically have been competitors not collaborators, are still the exception and not the rule. “We’ve created new models such as pre-competitive consortia that incentivize them to work with us as one without introducing any impediments to drug discovery and development.”

Since technologies around data sharing are rapidly evolving, MMRF has made it a priority to know the key players and build collaborations, particularly in the areas of data sharing via open access platforms, aggregation, and analysis.

Reports generated from the Know Your Tumor program often include therapeutic options that involve clinical trials. Matrisian explained that pharmaceutical companies are concerned with identifying patients with rare alterations who are appropriate for their trials. The pharmaceutical companies proactively follow up with patients for whom high-priority clinical trials are indicated and facilitate connecting these patients with trial site specialists.

 

FDA role in RWE

MMRF has worked closely with the FDA to help them understand what unmet need means in multiple myeloma, identify registrational opportunities for new indications and novel end points (such as minimal residual disease [MRD]), and innovate the design of clinical trials, explained Giusti.

The FDA is developing policy and publishing draft guidance on how RWE can be used to assess safety and effectiveness in both premarketing and postmarketing regulatory requirements. A recent NEJM opinion essay authored by FDA officials stated that RWE may most fundamentally be identified based on the context where the evidence is gathered, which includes clinical and home or community settings rather than research-intensive or academic environments.3

Fundamental issues that currently exist include confounding, data quality, and bias. The essay urged caution and tempering of expectations of “quick wins.” Robust methodological approaches are needed to address concerns about the unknown accuracy and reliability of RWE. Yet, optimism remains, as the FDA has acknowledged the potential of RWE to answer questions in rare diseases and provide valuable real-world insights.

 

References

  1. Blumenthal GM, Pazdur R. Approvals in 2016: the march of the checkpoint inhibitors. Nature Reviews Clinical Oncology. 2016; 14:131-132.
  2. Food and Drug Administration. PDUFA reauthorization performance goals and procedures fiscal years 2018 through 2022 (https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf).
  3. Sherman RE et al. Real-world evidence—what is it and what can it tell us? New England Journal of Medicine. 2016; 375:2293-2297.
  4. Reagan-Udal Foundation. Big Data for Patients (BD4P) (http://www.reaganudall.org/our-work/bd4p/).

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