FDA advances cancer treatments amid trial concerns

By Sarah Chacko – 11/23/16 5:50 AM ET

  • New cancer treatment combination with Darzalex found to reduce risk of progression or death. 
  • Cancer researchers say clinical trials do not represent patient populations in the real world. 

The Food and Drug Administration approved a new combination therapy for cancer, moving a drug that was once a fourth resort to a second-line treatment option.

However, some researchers have questioned the clinical trials drug approvals rely on, highlighting the importance of real world evidence, which is generated from data that is found in electronic health records, patient registries, insurance claims, surveys and mobile devices like smartphones and health trackers.

FDA announced Thursday that it has approved daratumumab, known commercially as Darzalex, in combination with other drugs for the treatment of patients with multiple myeloma who have received at least one prior therapy. Daratumumab was approved last November as single drug therapy for patients with multiple myeloma who have received at least three prior lines of therapy. 

In its announcement, FDA said the new approval was based on two randomized trials in which daratumumab was added to standard therapies. The two trials showed that adding daratumumab to specific drug pairs — lenalidomide and dexamethasone, and bortezomib and dexamethasone — reduced the risk of disease progression or death in patients by more than 60 percent.

The new approval came three months ahead of FDA’s deadline, via the agency’s expedited pathway for breakthrough therapy and orphan drugs, as well as priority review. 

Sufficient science?

A recent article in JAMA Oncology suggests that clinical trials do not represent patient populations in the real world; in particular, that they skew toward younger populations. Older patients experience more severe adverse side effects of treatments and are more likely to stop therapies, two cancer researchers from Memorial Sloan Kettering Cancer Center and Knight Cancer Institute said in the article. 

“There is evidence that the real-world use of novel anticancer drugs may fail to produce the benefits demonstrated in clinical trials,” the article states.

Jennifer Graff, vice president for comparative effectiveness research at the National Pharmaceutical Council (NPC), said FDA’s focus is typically on whether a drug can work, not if it works in all situations. The issue raised by the JAMA article is centers around effectiveness, “and that’s a more complicated question,” she said.

FDA uses real world evidence to monitor safety after a drug is on the market and published draft guidance this summer on the use of real world evidence to support regulatory decision making for medical devices.

FDA Commissioner Robert Califf said last week the agency would soon publish an article around the use of real world evidence in drug development. The upcoming reauthorization of the Prescription Drug User Fee Act also includes goals around enhancing the use of real world evidence in regulatory decisions, such as a deadline for draft guidance by fiscal 2021.

Real guidance

Graff said several groups have issued standards for the quality of real world data, but FDA has not signaled its approval of any particular one, making it hard for researchers to predict what federal regulators might find acceptable. 

The uncertainty may also keep insurers from covering certain drugs. Payers prefer to use randomized controlled trials instead of observational data to inform drug coverage decisions, NPC says.

FDA said in a statement to The Hill Extra that "encouraging the use of real-world data in regulatory decision making does not negate the need for high quality metrics and methods" used by the agency today.

Instead, the use of medical products should follow the label, which is based on a high evidentiary standard and focuses on use for an intended population, and the clinical practice guideline, which fills in the subjective information and nuance needed to make good treatment decisions.

"We welcome the discussion about real world evidence, but we also caution that real world evidence and clinical trials are not contradictory," FDA said in the statement, pointing to another JAMA articlepublished earlier this month on FDA and the Centers for Medicare and Medicaid Services efforts to expand and share the resources on which they base regulatory and coverage decision. "Clinical trials in the context of the real world is the approach that we are actively encouraging."

That line of thinking is similar to what FDA is exploring in so-called pragmatic clinical trials, which are like randomized trials but allow more flexibility around factors that differ in the real world, like dosing. FDA has used pragmatic trials, but it has not been a common or consistent practice across divisions, Graff said.

Other groups, such as the NIH Health Care Systems Research Collaboratory, have also raised concernsthat the detailed consent forms FDA requires for low-risk pragmatic clinical trials of investigational drugs and devices may dissuade patients from participating.

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