The Lynx Group

The Value of Personalized Medicine Lies in Evidence Thresholds, Drug Testing, and Pricing Trends

June 2014, Vol 5, No 5

Los Angeles, CA—Although targeted drug development and testing are clearly transforming medicine, resistance to greater uptake of personalized medicine includes a shift in the evidence threshold in personalized testing and drawbacks to the delivery system, including the cost of molecular tests, said Peter B. Bach, MD, Director, Center for Health Policy and Outcomes, Memorial Sloan Kettering Cancer Center, New York, at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

There are many obstacles to actualizing the value of personalized medicine, according to Dr Bach. The question is, how far and how soon could we get there? “Can we target tumors more precisely?” he asked. “Can we turn the immune system into our ally? Can we shut off critical mechanisms in cancer cell cycles in a way that has limited toxicity? Can we become more precise?”

Molecular Testing Is Changing
The traditional cancer treatment is based on an established test and disease characteristics, and insurers then work around the lack of specific coding for the test. For example, UnitedHealthcare instituted a program whereby the results of HER2 testing for breast cancer had to be communicated before trastuzumab treatment would be covered.

The payment action on the test was stopped until the test results were known, said Dr Bach. “That matters, and it also matters as we move toward this place where the tests themselves will be expensive. If you put the barricade after the test, then it’s going to have a different effect on utilization than if you do it before.”

The paradigm for cancer drug development, US Food and Drug Administration (FDA) approval, and labeling may eventually change from relaying on site of cancer, cancer stage, and cell type to mutation status or biologic pathway. “As we move forward, the FDA has been heavy-handed about saying that we’re going to live in a new age of paired diagnostics,” he said. Crizotinib was the prototype for this model, with the diagnostic test codeveloped with the drug manufacturer in the context of a clinical trial.

According to Dr Bach, however, the age of paired diagnostics may already be over, as the number of required tests and tissue samples becomes cumbersome. “We’re going to rapidly need to do too many assays and look for too many different mutations in any particular organ type for us to stick with a paired paradigm,” he said. “I think testing for multiple mutations at the same time in the tumor is where we’re going to end up.”

Building of Evidence
A shift in evidence gathering and utilization is taking place around personalized testing. HER2 testing errors occur in approximately 20% of samples, resulting in misclassification of patients. There are also many genetic alterations with similar biologic activity, and there is no gold standard in test development.

There are hundreds of targets and compounds. Tests are becoming a cost issue, often running into the thousands of dollars. “Payers are noticing the costs of these tests, and they’re trying to figure out what the standard should be for them,” said Dr Bach.

The tests are opening up a Pandora’s box in treatment: any mutation found anywhere could justify a trial of treatment. “There is a fear that it’s going to lead to wild experimentation without the capture of data, and I think that’s a legitimate one,” Dr Bach said.

Payers also have operational challenges, he said. Insurers generally cover tests under fairly simple rules that can be administered, such as obtaining a HER2 assay for breast cancer. But the new multigene tests are complex, as are the clinical scenarios. It is not clear that oncologists will know how to respond to the coming barrage of information.

The appropriate evidence standard remains open, said Dr Bach. Moving from a test result to improved outcome should be one standard, he argued. The evidence for off-label uses of agents should go beyond supposition, but randomized controlled trials are not feasible for every possibility. “We’re probably headed for a case series kind of approach,” Dr Bach said.

The FDA now often accelerates drug approval based on single-arm studies with surrogate end points (essentially case series). Imatinib, for example, was approved with evidence of cytogenetic changes on sequential case series, and ceritinib was approved on the basis of response rate in a single-arm trial.

These types of case series or patient registries are open to all patients, he said. “There’s no cherry picking; they enroll all comers.” They capture high-quality data with deep follow-up, with no bias introduced from loss to follow-up or end-point evaluation triggered by clinical events. Outcomes otherwise must be known from historical data.

Until evidence is built correctly, the default stance will be very conservative. “We have shown ourselves to be somewhat aggressive about pushing the envelope for using expensive therapies when they are not indicated, so the default is the resistance of 2 opposing forces,” Dr Bach said.

Drug Pricing Trends
Pricing trends are also a problem, with monthly and median costs of cancer drugs at the time of FDA approval increasing exponentially over the years (Figure). “Any issue we have with off-label use of drugs that are targeted is going to get worse as the prices go higher,” Dr Bach said.

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